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<title>
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Entry
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- *137070 - FUS RNA-BINDING PROTEIN; FUS
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- OMIM
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</ul>
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</nav>
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</div>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
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<div class="form-group">
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<div class="input-group">
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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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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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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>
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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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<li role="separator" class="divider"></li>
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<li>
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<a href="/history"> Search History </a>
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</ul>
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</div>
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</div>
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<div class="autocomplete" id="mimEntrySearchAutocomplete"></div>
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</form>
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<div class="row">
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<p />
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</div>
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<!-- <div id="mimSearch"> -->
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*137070</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="#cytogenetics">Cytogenetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/137070">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
|
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<h4 class="panel-title">
|
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
|
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<div style="display: table-row">
|
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
|
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</a>
|
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</h4>
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</div>
|
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
|
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</span>
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</span>
|
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</div>
|
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000089280;t=ENST00000254108" 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=2521" 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=137070" 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=ENSG00000089280;t=ENST00000254108" 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_001170634,NM_001170937,NM_004960,NR_028388,XM_011545781,XM_011545782,XM_024450221" 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_004960" 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=137070" 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=00660&isoform_id=00660_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/FUS" 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/386157,544357,1040970,3582783,3582784,4210363,4826734,12653267,12803287,19913512,30583101,34481863,48145611,62087384,119572535,119572536,119572537,158255308,194375193,194386744,283135173,283135201,767988385,767988388,1240949362,1370468244,1387146611,1989124422,2462548319,2462548321,2462548323" 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/P35637" 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=2521" 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=ENSG00000089280;t=ENST00000254108" 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=FUS" 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=FUS" 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+2521" 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/FUS" 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:2521" 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/2521" 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=chr16&hgg_gene=ENST00000254108.12&hgg_start=31180110&hgg_end=31194871&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:4010" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/fus" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=137070[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=137070[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/ENSG00000089280" 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.gwascentral.org/search?q=FUS" 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=FUS" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.molgen.ua.ac.be/ADMutations/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=FUS&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/PA28425" 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:4010" 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/FBgn0037939.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:1353633" 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/FUS#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:1353633" 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/2521/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=2521" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00016173;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040426-1010" 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:2521" 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=FUS&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> 1204334005<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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137070
|
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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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FUS RNA-BINDING PROTEIN; FUS
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</span>
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</h3>
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</div>
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<div>
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
FUSED IN SARCOMA<br />
|
|
FUSION, DERIVED FROM 12-16 TRANSLOCATION, MALIGNANT LIPOSARCOMA<br />
|
|
TRANSLOCATED IN LIPOSARCOMA; TLS
|
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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">
|
|
Other entities represented in this entry:
|
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</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
FUS/ATF1 FUSION GENE, INCLUDED
|
|
</span>
|
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</div>
|
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<div>
|
|
<span class="h4 mim-font">
|
|
|
|
FUS/CHOP FUSION GENE, INCLUDED<br />
|
|
FUS/ERG FUSION GENE, INCLUDED<br />
|
|
FUS/CREB3L2 FUSION GENE, INCLUDED
|
|
</span>
|
|
</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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=FUS" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FUS</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/16/384?start=-3&limit=10&highlight=384">16p11.2</a>
|
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:31180110-31194871&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'})">16:31,180,110-31,194,871</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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Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia
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Essential tremor, hereditary, 4
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/radial/137070" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>FUS is a nucleoprotein that functions in DNA and RNA metabolism, including DNA repair, and the regulation of transcription, RNA splicing, and export to the cytoplasm. Translocation of the FUS transcriptional activation domain results in fusion proteins and has been implicated in tumorigenesis (summary by <a href="#33" class="mim-tip-reference" title="Vance, C., Rogelj, B., Hortobagyi, T., De Vos, K. J., Nishimura, A. L., Sreedharan, J., Hu, X., Smith, B., Ruddy, D., Wright, P., Ganesalingam, J., Williams, K. L., and 10 others. <strong>Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6.</strong> Science 323: 1208-1211, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19251628[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1165942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251628">Vance et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19251628" 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="#25" class="mim-tip-reference" title="Rabbitts, T. H., Forster, A., Larson, R., Nathan, P. <strong>Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma.</strong> Nature Genet. 4: 175-180, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7503811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7503811</a>] [<a href="https://doi.org/10.1038/ng0693-175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7503811">Rabbitts et al. (1993)</a> identified the FUS gene as part of a fusion gene with the transcription factor gene CHOP (DDIT3; <a href="/entry/126337">126337</a>) in tumor tissue derived from 2 patients with liposarcomas carrying t(12;16)(q13;p11) translocations. Nucleotide and derived protein sequences of the FUS gene were determined by isolating the gene from a cDNA library. The deduced 525-residue protein contains 3 glycine clusters and 6 potential N-linked glycosylation sites. <a href="#25" class="mim-tip-reference" title="Rabbitts, T. H., Forster, A., Larson, R., Nathan, P. <strong>Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma.</strong> Nature Genet. 4: 175-180, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7503811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7503811</a>] [<a href="https://doi.org/10.1038/ng0693-175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7503811">Rabbitts et al. (1993)</a> postulated that the fusion gene disrupted transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7503811" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Crozat, A., Aman, P., Mandahl, N., Ron, D. <strong>Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma.</strong> Nature 363: 640-644, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8510758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8510758</a>] [<a href="https://doi.org/10.1038/363640a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8510758">Crozat et al. (1993)</a> independently identified the FUS gene, which they termed 'TLS' for translocated in liposarcoma, in tissue tumor of human myxoid liposarcoma. The TLS gene was also fused with CHOP. The full-length TLS gene encodes a 526-amino acid protein. Western blot analysis detected TLS as a 68-kD band. They noted that a 1.9- to 2.0-kb transcript was detected in all cell lines and tissues examined. TLS was shown to be a nuclear RNA-binding protein with extensive sequence similarity to EWSR1 (<a href="/entry/133450">133450</a>), the product of a gene commonly translocated in Ewing sarcoma (<a href="/entry/612219">612219</a>). In the TLS/CHOP fusion gene, the RNA-binding domain of TLS was replaced by the DNA-binding and leucine zipper dimerization domain of CHOP. <a href="#6" class="mim-tip-reference" title="Crozat, A., Aman, P., Mandahl, N., Ron, D. <strong>Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma.</strong> Nature 363: 640-644, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8510758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8510758</a>] [<a href="https://doi.org/10.1038/363640a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8510758">Crozat et al. (1993)</a> suggested that the fusion protein caused a disruption in transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8510758" 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="#34" class="mim-tip-reference" title="Vance, C., Scotter, E. L., Nishimura, A. L., Troakes, C., Mitchell, J. C., Kathe, C., Urwin, H., Manser, C., Miller, C. C., Hortobagyi, T., Dragunow, M., Rogelj, B., Shaw, C. E. <strong>ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within cytoplasmic stress granules.</strong> Hum. Molec. Genet. 22: 2676-2688, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23474818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23474818</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23474818[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/ddt117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23474818">Vance et al. (2013)</a> reported that the full-length 526-amino acid FUS protein contains an N-terminal serine-, tyrosine-, glycine-, and glutamine-rich domain, followed by a glycine-rich region, an RNA recognition motif, and a zinc finger domain. Interspersed between these domains are 3 RGG repeat regions. <a href="#34" class="mim-tip-reference" title="Vance, C., Scotter, E. L., Nishimura, A. L., Troakes, C., Mitchell, J. C., Kathe, C., Urwin, H., Manser, C., Miller, C. C., Hortobagyi, T., Dragunow, M., Rogelj, B., Shaw, C. E. <strong>ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within cytoplasmic stress granules.</strong> Hum. Molec. Genet. 22: 2676-2688, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23474818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23474818</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23474818[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/ddt117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23474818">Vance et al. (2013)</a> determined that FUS also has a C-terminal proline-tyrosine nuclear localization signal. Epitope-tagged FUS localized predominantly to the nucleus of transfected human neuroblastoma cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23474818" 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="#1" class="mim-tip-reference" title="Aman, P., Panagopoulos, I., Lassen, C., Fioretos, T., Mencinger, M., Toresson, H., Hoglund, M., Forster, A., Rabbitts, T. H., Ron, D., Mandahl, N., Mitelman, F. <strong>Expression patterns of the human sarcoma-associated genes FUS and EWS and the genomic structure of FUS.</strong> Genomics 37: 1-8, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8921363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8921363</a>] [<a href="https://doi.org/10.1006/geno.1996.0513" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8921363">Aman et al. (1996)</a> defined the genomic structure of FUS and compared it with the structure of EWSR1. The FUS gene contains 15 exons located within 11 kb of genomic DNA. FUS exon 1 contains a 72-bp untranslated region and the translation initiation codon. Multiple glycine repeats occurred in a number of positions in the gene, and an RNP region was encoded by exons 9, 10 and 11. The exon/intron structures of FUS and EWSR1 showed extensive similarities in the RNP regions, suggesting that the 2 genes may have been derived from a common ancestor. The sequence upstream of the FUS transcription start site contained no TATA boxes but did contain stretches of C and G. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8921363" 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="#20" class="mim-tip-reference" title="Morohoshi, F., Ootsuka, Y., Arai, K., Ichikawa, H., Mitani, S., Munakata, N., Ohki, M. <strong>Genomic structure of the human RBP56/hTAF(II)68 and FUS/TLS genes.</strong> Gene 221: 191-198, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9795213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9795213</a>] [<a href="https://doi.org/10.1016/s0378-1119(98)00463-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9795213">Morohoshi et al. (1998)</a> determined that the FUS gene spans 12 kb. They noted that the conservation of the overall exon number and structure of RBP56 (<a href="/entry/601574">601574</a>), FUS, and EWSR1 indicates that they probably originated from the same ancestral gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9795213" 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="#6" class="mim-tip-reference" title="Crozat, A., Aman, P., Mandahl, N., Ron, D. <strong>Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma.</strong> Nature 363: 640-644, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8510758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8510758</a>] [<a href="https://doi.org/10.1038/363640a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8510758">Crozat et al. (1993)</a> localized the FUS gene to chromosome 16p11 by analyzing the site of the breakpoint of translocation in Ewing sarcoma. The assignment was further narrowed to 16p11.2 by cytogenetic studies of <a href="#9" class="mim-tip-reference" title="Eneroth, M., Mandahl, N., Heim, S., Willen, H., Rydholm, A., Alberts, K. A., Mitelman, F. <strong>Localization of the chromosomal breakpoints of the t(12;16) in liposarcoma to subbands 12q13.3 and 16p11.2.</strong> Cancer Genet. Cytogenet. 48: 101-107, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2372777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2372777</a>] [<a href="https://doi.org/10.1016/0165-4608(90)90222-v" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2372777">Eneroth et al. (1990)</a> and of <a href="#21" class="mim-tip-reference" title="Mrozek, K., Karakousis, C. P., Bloomfield, C. D. <strong>Chromosome 12 breakpoints are cytogenetically different in benign and malignant lipogenic tumors: localization of breakpoints in lipoma to 12q15 and in myxoid liposarcoma to 12q13.3.</strong> Cancer Res. 53: 1670-1675, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8453640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8453640</a>]" pmid="8453640">Mrozek et al. (1993)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2372777+8510758+8453640" 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="#1" class="mim-tip-reference" title="Aman, P., Panagopoulos, I., Lassen, C., Fioretos, T., Mencinger, M., Toresson, H., Hoglund, M., Forster, A., Rabbitts, T. H., Ron, D., Mandahl, N., Mitelman, F. <strong>Expression patterns of the human sarcoma-associated genes FUS and EWS and the genomic structure of FUS.</strong> Genomics 37: 1-8, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8921363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8921363</a>] [<a href="https://doi.org/10.1006/geno.1996.0513" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8921363">Aman et al. (1996)</a> found that the N-terminal ends of FUS and EWSR1 differed, but they shared extensive homology and were distinct from the N-terminal regions of other RNP-carrying proteins, suggesting that FUS and EWSR1 could be regarded as the first members of a new family of RNA-binding proteins. Several recognition sites for the transcription factors AP2 (<a href="/entry/107580">107580</a>), GCF (<a href="/entry/189901">189901</a>), and Sp1 (<a href="/entry/189906">189906</a>) were identified in FUS. <a href="#1" class="mim-tip-reference" title="Aman, P., Panagopoulos, I., Lassen, C., Fioretos, T., Mencinger, M., Toresson, H., Hoglund, M., Forster, A., Rabbitts, T. H., Ron, D., Mandahl, N., Mitelman, F. <strong>Expression patterns of the human sarcoma-associated genes FUS and EWS and the genomic structure of FUS.</strong> Genomics 37: 1-8, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8921363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8921363</a>] [<a href="https://doi.org/10.1006/geno.1996.0513" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8921363">Aman et al. (1996)</a> stressed that the nature of the promoter regions of FUS and EWSR1 is important for understanding the control of the fusion genes involving FUS and EWSR1 in tumors. All tumor-specific translocations resulted in the formation of fusion genes with FUS or EWSR1 promoter regions and 5-prime coding regions linked to transcription factor genes. Thus, the transcriptional control of the fusion genes is most likely dominated by the FUS and EWS promoters. <a href="#1" class="mim-tip-reference" title="Aman, P., Panagopoulos, I., Lassen, C., Fioretos, T., Mencinger, M., Toresson, H., Hoglund, M., Forster, A., Rabbitts, T. H., Ron, D., Mandahl, N., Mitelman, F. <strong>Expression patterns of the human sarcoma-associated genes FUS and EWS and the genomic structure of FUS.</strong> Genomics 37: 1-8, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8921363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8921363</a>] [<a href="https://doi.org/10.1006/geno.1996.0513" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8921363">Aman et al. (1996)</a> reported that exons 1 to 5 of FUS are invariably present in tumor-associated fusion proteins involving FUS. The tumor breakpoints in the EWSR1 and FUS genes are all localized in the same regions of the genes, upstream of the RNP encoding exons. FUS and EWSR1 were expressed in all tissues examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8921363" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The leukemogenic potential of BCR (<a href="/entry/151410">151410</a>)/ABL (<a href="/entry/189980">189980</a>) oncoproteins depends on their tyrosine kinase activity and involves the activation of several downstream effectors, some of which are essential for cell transformation. Using electrophoretic mobility shift assays and Southwestern blot analyses with a double-stranded oligonucleotide containing a zinc finger consensus sequence, <a href="#24" class="mim-tip-reference" title="Perrotti, D., Bonatti, S., Trotta, R., Martinez, R., Skorski, T., Salomoni, P., Grassilli, E., Iozzo, R. V., Cooper, D. R., Calabretta, B. <strong>TLS/FUS, a pro-oncogene involved in multiple chromosomal translocations, is a novel regulator of BCR/ABL-mediated leukemogenesis.</strong> EMBO J. 17: 4442-4455, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9687511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9687511</a>] [<a href="https://doi.org/10.1093/emboj/17.15.4442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9687511">Perrotti et al. (1998)</a> identified a 68-kD DNA-binding protein specifically induced by BCR/ABL. The peptide sequence of the affinity-purified protein was identical to that of the RNA-binding protein FUS. Binding activity of FUS required a functional BCR/ABL tyrosine kinase necessary to induce PRKCB2 (see <a href="/entry/176970">176970</a>)-dependent FUS phosphorylation. Moreover, suppression of PRKCB2 activity in BCR/ABL-expressing cells by treatment with the PRKCB2 inhibitor CGP53353, or by expression of a dominant-negative PRKCB2, markedly impaired the ability of FUS to bind DNA. Suppression of FUS expression in myeloid precursor 32Dcl3 cells transfected with a FUS antisense construct was associated with upregulation of the granulocyte colony-stimulating factor receptor (GCSFR; <a href="/entry/138971">138971</a>) and downregulation of interleukin-3 receptor beta-chain (IL3RB; <a href="/entry/138981">138981</a>) expression, and accelerated GCSF (<a href="/entry/138970">138970</a>)-stimulated differentiation. Downregulation of FUS expression in BCR/ABL-expressing 32Dcl3 cells was associated with suppression of growth factor-independent colony formation, restoration of GCSF-induced granulocytic differentiation, and reduced tumorigenic potential in vivo. <a href="#24" class="mim-tip-reference" title="Perrotti, D., Bonatti, S., Trotta, R., Martinez, R., Skorski, T., Salomoni, P., Grassilli, E., Iozzo, R. V., Cooper, D. R., Calabretta, B. <strong>TLS/FUS, a pro-oncogene involved in multiple chromosomal translocations, is a novel regulator of BCR/ABL-mediated leukemogenesis.</strong> EMBO J. 17: 4442-4455, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9687511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9687511</a>] [<a href="https://doi.org/10.1093/emboj/17.15.4442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9687511">Perrotti et al. (1998)</a> suggested that FUS might function as a regulator of BCR/ABL leukemogenesis, promoting growth factor independence and preventing differentiation via modulation of cytokine receptor expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9687511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By Western blot analysis, <a href="#39" class="mim-tip-reference" title="Yang, L., Embree, L. J., Hickstein, D. D. <strong>TLS-ERG leukemia fusion protein inhibits RNA splicing mediated by serine-arginine proteins.</strong> Molec. Cell. Biol. 20: 3345-3354, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10779324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10779324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10779324[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/10.1128/MCB.20.10.3345-3354.2000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10779324">Yang et al. (2000)</a> showed that the N-terminal domain of TLS binds to RNA polymerase II and that this binding was retained by the TLS/ERG (<a href="/entry/165080">165080</a>) fusion protein. However, the C-terminal domain of TLS was required for interaction with the serine-arginine (SR) splicing factor SC35 (SFRS2; <a href="/entry/600813">600813</a>) and the TLS-associated SR proteins TASR1 and TASR2; this binding was lost in the TLS/ERG fusion protein because ERG replaced the C terminus of TLS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10779324" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Wang, X., Arai, S., Song, X., Reichart, D., Du, K., Pascual, G., Tempst, P., Rosenfeld, M. G., Glass, C. K., Kurokawa, R. <strong>Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription.</strong> Nature 454: 126-130, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18509338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18509338</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18509338[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature06992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18509338">Wang et al. (2008)</a> showed that an RNA-binding protein, TLS, serves as a key transcriptional regulatory sensor of DNA damage signals that, on the basis of its allosteric modulation by RNA, specifically binds to and inhibits CREB-binding protein (CBP; <a href="/entry/600140">600140</a>) and p300 histone acetyltransferase (<a href="/entry/602700">602700</a>) activities on a repressed gene target, cyclin D1 (CCND1; <a href="/entry/168461">168461</a>), in human cell lines. Recruitment of TLS to the CCND1 promoter to cause gene-specific repression is directed by single-stranded, low copy-number noncoding RNA (ncRNA) transcripts tethered to the 5-prime regulatory regions of CCND1 that are induced in response to DNA damage signals. <a href="#36" class="mim-tip-reference" title="Wang, X., Arai, S., Song, X., Reichart, D., Du, K., Pascual, G., Tempst, P., Rosenfeld, M. G., Glass, C. K., Kurokawa, R. <strong>Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription.</strong> Nature 454: 126-130, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18509338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18509338</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18509338[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature06992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18509338">Wang et al. (2008)</a> suggested that signal-induced noncoding RNAs localized to regulatory regions of transcription units can act cooperatively as selective ligands, recruiting and modulating the activities of distinct classes of RNA-binding coregulators in response to specific signals, providing an unexpected noncoding RNA/RNA-binding protein-based strategy to integrate transcriptional programs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18509338" 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 human prooncoprotein TLS purified from HeLa nuclear extracts, <a href="#2" class="mim-tip-reference" title="Baechtold, H., Kuroda, M., Sok, J., Ron, D., Lopez, B. S., Akhmedov, A. T. <strong>Human 75-kDa DNA-pairing protein is identical to the pro-oncoprotein TLS/FUS and is able to promote D-loop formation.</strong> J. Biol. Chem. 274: 34337-34342, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10567410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10567410</a>] [<a href="https://doi.org/10.1074/jbc.274.48.34337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10567410">Baechtold et al. (1999)</a> showed that TLS binds both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), with a 2-fold higher affinity for ssDNA. TLS can mediate the annealing of complementary ssDNAs, and this reaction requires Mg(2+), but not ATP. TLS was also found to promote the formation of stable D-loops in a homology-dependent manner during homologous recombination, again in the presence of Mg(2+), but not ATP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10567410" 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="Lerga, A., Hallier, M., Delva, L., Orvain, C., Gallais, I., Marie, J., Moreau-Gachelin, F. <strong>Identification of an RNA binding specificity for the potential splicing factor TLS.</strong> J. Biol. Chem. 276: 6807-6816, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11098054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11098054</a>] [<a href="https://doi.org/10.1074/jbc.M008304200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11098054">Lerga et al. (2001)</a> found that TLS specifically recognized RNA sequences containing a GGUG motif both in vitro and in vivo, and the specificity was determined by the cooperation between the RRM and RGG RNA binding domains of TLS. Analysis of TLS deletion mutants expressed in IW1-32 erythroid cells showed that these RNA binding domains of TLS are also responsible for the functional interference of TLS with in vivo splicing of pre-mRNAs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11098054" 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="Doi, H., Okamura, K., Bauer, P. O., Furukawa, Y., Shimizu, H., Kurosawa, M., Machida, Y., Miyazaki, H., Mitsui, K., Kuroiwa, Y., Nukina, N. <strong>RNA-binding protein TLS is a major nuclear aggregate-interacting protein in huntingtin exon 1 with expanded polyglutamine-expressing cells.</strong> J. Biol. Chem. 283: 6489-6500, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18167354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18167354</a>] [<a href="https://doi.org/10.1074/jbc.M705306200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18167354">Doi et al. (2008)</a> found that TLS is one of the major nuclear polyQ aggregate-interacting proteins in a Huntington disease (HD; <a href="/entry/143100">143100</a>) cell model, and binds directly to nuclear polyQ aggregates through its QSY-rich domain. Monitoring the kinetics of amyloid formation of expanded polyQ proteins in vitro and in vivo revealed that TLS inhibits polyQ aggregate growth. Further analysis demonstrated that TLS binding to polyQ amyloid and amorphous aggregates takes place at an early stage and interferes with amyloid formation before the formation of amyloid fibrils. Examination of polyQ aggregates in HD transgenic mouse brain revealed that TLS colocalizes with neuronal intranuclear inclusions (NIIs). Immunohistochemistry showed that TLS binds to neuronal intranuclear inclusions of human HD brain, suggesting that TLS participates in the pathogenesis of polyQ diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18167354" 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="#13" class="mim-tip-reference" title="Ichikawa, H., Shimizu, K., Hayashi, Y., Ohki, M. <strong>An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation.</strong> Cancer Res. 54: 2865-2868, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8187069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8187069</a>]" pmid="8187069">Ichikawa et al. (1994)</a> and <a href="#22" class="mim-tip-reference" title="Panagopoulos, I., Aman, P., Fioretos, T., Hoglund, M., Johansson, B., Mandahl, N., Heim, S., Behrendtz, M., Mitelman, F. <strong>Fusion of the FUS gene with ERG in acute myeloid leukemia with t(16;21)(p11;q22).</strong> Genes Chromosomes Cancer 11: 256-262, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7533529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7533529</a>] [<a href="https://doi.org/10.1002/gcc.2870110408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7533529">Panagopoulos et al. (1994)</a> reported that the FUS gene was fused to the ERG gene in a patient with acute myeloid leukemia with a translocation t(16:21)(p11;q22). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7533529+8187069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Waters, B. L., Panagopoulos, I., Allen, E. F. <strong>Genetic characterization of angiomatoid fibrous histiocytoma identifies fusion of the FUS and ATF-1 genes induced by a chromosomal translocation involving bands 12q13 and 16p11.</strong> Cancer Genet. Cytogenet. 121: 109-116, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11063792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11063792</a>] [<a href="https://doi.org/10.1016/s0165-4608(00)00237-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11063792">Waters et al. (2000)</a> described a 5.5-year-old girl who presented with a firm mass in her left forearm diagnosed as an angiomatoid fibrous histiocytoma (<a href="/entry/612160">612160</a>). Analysis of tumor tissue showed complex rearrangements between chromosomes 2, 12, 16, and 17 were noted on karyotypic study, as well as deletion in the long arm of chromosome 11. A t(12;16) site was investigated using RT-PCR. The FUS gene at 16p11.2 was found to be combined with the ATF1 gene (<a href="/entry/123803">123803</a>) at 12q13, generating a chimeric FUS/ATF1. <a href="#37" class="mim-tip-reference" title="Waters, B. L., Panagopoulos, I., Allen, E. F. <strong>Genetic characterization of angiomatoid fibrous histiocytoma identifies fusion of the FUS and ATF-1 genes induced by a chromosomal translocation involving bands 12q13 and 16p11.</strong> Cancer Genet. Cytogenet. 121: 109-116, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11063792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11063792</a>] [<a href="https://doi.org/10.1016/s0165-4608(00)00237-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11063792">Waters et al. (2000)</a> found that FUS was interrupted at codon 175 and fused to codon 110 of ATF1, resulting in an in-frame junction with a glycine-to-valine (GGT-to-GTT) transition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11063792" 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>Low-grade fibromyxoid sarcoma (LGFMS) is a variant of fibrosarcoma. In 2 cases of soft tissue sarcoma that fulfilled morphologic criteria for LGFMS, <a href="#32" class="mim-tip-reference" title="Storlazzi, C. T., Mertens, F., Nascimento, A., Isaksson, M., Wejde, J., Brosjo, O., Mandahl, N., Panagopoulos, I. <strong>Fusion of the FUS and BBF2H7 genes in low grade fibromyxoid sarcoma.</strong> Hum. Molec. Genet. 12: 2349-2358, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915480</a>] [<a href="https://doi.org/10.1093/hmg/ddg237" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915480">Storlazzi et al. (2003)</a> identified an FUS/CREB3L2 (<a href="/entry/608834">608834</a>) chimera, caused by a translocation between chromosome bands 7q33-q34 (CREB3L2) and 16p11 (FUS). A t(7;16)(q34;p11) translocation with the same or similar breakpoints had previously been reported in 5 other cases of LGFMS (<a href="#3" class="mim-tip-reference" title="Bejarano, P. A., Padhya, T. A., Smith, R., Blough, R., Devitt, J. J., Gluckman, J. L. <strong>Hyalinizing spindle cell tumor with giant rosettes--a soft tissue tumor with mesenchymal and neuroendocrine features: an immunohistochemical, ultrastructural, and cytogenetic analysis.</strong> Arch. Path. Lab. Med. 124: 1179-1184, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10923080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10923080</a>] [<a href="https://doi.org/10.5858/2000-124-1179-HSCTWG" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10923080">Bejarano et al., 2000</a>; <a href="#27" class="mim-tip-reference" title="Reid, R., de Silva, M. V. C., Paterson, L., Ryan, E., Fisher, C. <strong>Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes share a common t(7;16)(q34;p11) translocation.</strong> Am. J. Surg. Path. 27: 1229-1236, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960807</a>] [<a href="https://doi.org/10.1097/00000478-200309000-00006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12960807">Reid et al., 2003</a>). To delineate the spectrum of tumors that may harbor the FUS/CREB3L2 fusion gene, <a href="#23" class="mim-tip-reference" title="Panagopoulos, I., Storlazzi, C. T., Fletcher, C. D. M., Fletcher, J. A., Nascimento, A., Domanski, H. A., Wejde, J., Brosjo, O., Rydholm, A., Isaksson, M., Mandahl, N., Mertens, F. <strong>The chimeric FUS/CREB3L2 gene is specific for low-grade fibromyxoid sarcoma.</strong> Genes Chromosomes Cancer 40: 218-228, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15139001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15139001</a>] [<a href="https://doi.org/10.1002/gcc.20037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15139001">Panagopoulos et al. (2004)</a> selected 45 low-grade spindle cell sarcomas for study. None of these tumors had originally been diagnosed as LGFMS. Fourteen other tumors were also analyzed: 2 benign soft tissue tumors, 9 high-grade sarcomas with supernumerary ring chromosomes or 7q3 rearrangement, and 3 tumors diagnosed as LGFMS prior to genetic analysis. Of the 59 tumors studied, 12 were FUS/CREB3L2-positive, all of which were diagnosed at histopathologic reexamination as being LGFMS, of both the classic subtype and the subtype with giant collagen rosettes. The breakpoints in the fusion transcripts were always in exons 6 or 7 of FUS and exon 5 of CREB3L2. In the FUS/CREB3L2 chimera, the DNA binding and basic leucine zipper dimerization (bZIP)-encoding domain of CREB3L2 comes under the control of the FUS promoter, which, in turn, may cause deregulation of genes normally controlled by CREB3L2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15139001+10923080+12915480+12960807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Amyotrophic Lateral Sclerosis 6</em></strong></p><p>
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<a href="#15" class="mim-tip-reference" title="Lattante, S., Rouleau, G. A., Kabashi, E. <strong>TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary and update.</strong> Hum. Mutat. 34: 812-826, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23559573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23559573</a>] [<a href="https://doi.org/10.1002/humu.22319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23559573">Lattante et al. (2013)</a> provided a review of FUS mutations associated with amyotrophic lateral sclerosis (ALS6; <a href="/entry/608030">608030</a>). FUS mutations occur in about 5% of patients with familial ALS and in 1% of patients with sporadic disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23559573" 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 17 different families with amyotrophic lateral sclerosis-6 (ALS6; <a href="/entry/608030">608030</a>), <a href="#14" class="mim-tip-reference" title="Kwiatkowski, T. J., Jr., Bosco, D. A., LeClerc, A.L., Tamrazian, E., Vanderburg, C. R., Russ, C., Davis, A., Gilchrist, J., Kasarskis, E. J., Munsat, T., Valdmanis, P., Rouleau, G. A., and 14 others. <strong>Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.</strong> Science 323: 1205-1208, 2009. Note: Erratum: Science 324: 465 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251627</a>] [<a href="https://doi.org/10.1126/science.1166066" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251627">Kwiatkowski et al. (2009)</a> identified 13 different mutations in the FUS gene (see, e.g., <a href="#0001">137070.0001</a>-<a href="#0004">137070.0004</a>), including 10 mutations in exon 15. Only 1 mutation (<a href="#0001">137070.0001</a>) was found in homozygosity. Postmortem examination of 1 patient with the R521G mutation (<a href="#0002">137070.0002</a>) showed loss of motor neurons in the anterior horn of the spinal cord and the hypoglossal nucleus. Immunostaining showed nuclear and cytoplasmic aggregation of FUS and diffuse ubiquitin positivity in nuclei in the patient tissue, but not control tissue, suggesting misfolding of a nuclear protein. In vitro RNA binding studies showed that the mutations did not affect binding of RNA oligomers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19251627" 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="#33" class="mim-tip-reference" title="Vance, C., Rogelj, B., Hortobagyi, T., De Vos, K. J., Nishimura, A. L., Sreedharan, J., Hu, X., Smith, B., Ruddy, D., Wright, P., Ganesalingam, J., Williams, K. L., and 10 others. <strong>Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6.</strong> Science 323: 1208-1211, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19251628[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1165942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251628">Vance et al. (2009)</a> identified 3 FUS mutations in 9 families with ALS6. All of the mutations had also been found by <a href="#14" class="mim-tip-reference" title="Kwiatkowski, T. J., Jr., Bosco, D. A., LeClerc, A.L., Tamrazian, E., Vanderburg, C. R., Russ, C., Davis, A., Gilchrist, J., Kasarskis, E. J., Munsat, T., Valdmanis, P., Rouleau, G. A., and 14 others. <strong>Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.</strong> Science 323: 1205-1208, 2009. Note: Erratum: Science 324: 465 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251627</a>] [<a href="https://doi.org/10.1126/science.1166066" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251627">Kwiatkowski et al. (2009)</a>. <a href="#33" class="mim-tip-reference" title="Vance, C., Rogelj, B., Hortobagyi, T., De Vos, K. J., Nishimura, A. L., Sreedharan, J., Hu, X., Smith, B., Ruddy, D., Wright, P., Ganesalingam, J., Williams, K. L., and 10 others. <strong>Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6.</strong> Science 323: 1208-1211, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19251628[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1165942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251628">Vance et al. (2009)</a> demonstrated that wildtype endogenous FUS is predominantly localized to the nucleus. FUS mutations caused subcellular mislocalization with protein retention in the cytoplasm. <a href="#14" class="mim-tip-reference" title="Kwiatkowski, T. J., Jr., Bosco, D. A., LeClerc, A.L., Tamrazian, E., Vanderburg, C. R., Russ, C., Davis, A., Gilchrist, J., Kasarskis, E. J., Munsat, T., Valdmanis, P., Rouleau, G. A., and 14 others. <strong>Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.</strong> Science 323: 1205-1208, 2009. Note: Erratum: Science 324: 465 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251627</a>] [<a href="https://doi.org/10.1126/science.1166066" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251627">Kwiatkowski et al. (2009)</a> and <a href="#33" class="mim-tip-reference" title="Vance, C., Rogelj, B., Hortobagyi, T., De Vos, K. J., Nishimura, A. L., Sreedharan, J., Hu, X., Smith, B., Ruddy, D., Wright, P., Ganesalingam, J., Williams, K. L., and 10 others. <strong>Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6.</strong> Science 323: 1208-1211, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19251628[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1165942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251628">Vance et al. (2009)</a> estimated the frequency of FUS mutations to be about 5% in familial ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19251627+19251628" 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="Corrado, L., Del Bo, R., Castellotti, B., Ratti, A., Cereda, C., Penco, S., Soraru, G., Carlomagno, Y., Ghezzi, S., Pensato, V., Colombrita, C., Gagliardi, S., and 10 others. <strong>Mutations of FUS gene in sporadic amyotrophic lateral sclerosis.</strong> J. Med. Genet. 47: 190-194, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19861302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19861302</a>] [<a href="https://doi.org/10.1136/jmg.2009.071027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19861302">Corrado et al. (2010)</a> identified 7 different missense mutations, including 6 novel mutations, in the FUS gene (see, e.g., <a href="#0006">137070.0006</a> and <a href="#0007">137070.0007</a>) in 9 of 1,009 Italian patients with ALS, including 964 patients with sporadic disease. Two of the 9 patients with an FUS mutation had a family history of the disorder. In addition, 8 different deletions and 2 insertions were identified in 2 glycine-rich regions in exons 5 and 6, but these were also found in controls and believed to represent triplet repeat length polymorphisms. Overall, pathogenic FUS mutations were found in 0.7% of sporadic and 4.4% of familial ALS in this population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19861302" 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="#11" class="mim-tip-reference" title="Hewitt, C., Kirby, J., Highley, J. R., Hartley, J. A., Hibberd, R., Hollinger, H. C., Williams, T. L., Ince, P. G., McDermott, C. J., Shaw, P. J. <strong>Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis.</strong> Arch. Neurol. 67: 455-461, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20385912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20385912</a>] [<a href="https://doi.org/10.1001/archneurol.2010.52" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20385912">Hewitt et al. (2010)</a> identified a heterozygous mutation in the FUS gene (<a href="#0008">137070.0008</a>) in 2 (5%) of 42 patients with familial ALS. A different heterozygous mutation (<a href="#0006">137070.0006</a>) was identified in 1 of 548 patients with sporadic ALS. Both mutations were located in the C-terminal region of the protein, which is important in regulating DNA and RNA binding. <a href="#11" class="mim-tip-reference" title="Hewitt, C., Kirby, J., Highley, J. R., Hartley, J. A., Hibberd, R., Hollinger, H. C., Williams, T. L., Ince, P. G., McDermott, C. J., Shaw, P. J. <strong>Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis.</strong> Arch. Neurol. 67: 455-461, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20385912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20385912</a>] [<a href="https://doi.org/10.1001/archneurol.2010.52" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20385912">Hewitt et al. (2010)</a> postulated that disruption of this region may disrupt subcellular distribution of FUS, in turn affecting transcription and RNA processing and conferring a toxic gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20385912" 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="#19" 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 5 different FUS mutations in 7 (4.3%) of 162 French probands with familial ALS. All mutations were located in exon 15 of the FUS gene. One patient with a FUS mutation (R521C; <a href="#0004">137070.0004</a>) was also heterozygous for a mutation in the ANG gene (K17I; <a href="/entry/105850#0002">105850.0002</a>), which causes ALS9 (<a href="/entry/611895">611895</a>). Overall, FUS mutation carriers had an earlier age of disease onset and shorter life span compared to those with mutations in other ALS genes. <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="#35" class="mim-tip-reference" title="Waibel, S., Neumann, M., Rabe, M., Meyer, T., Ludolph, A. C. <strong>Novel missense and truncating mutations in FUL/TLS in familial ALS.</strong> Neurology 75: 815-817, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20660363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20660363</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181f07e26" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20660363">Waibel et al. (2010)</a> identified 2 different heterozygous mutations in the FUS gene (see, e.g., R495X; <a href="#0009">137070.0009</a>) in 4 (6.8%) of 58 German families with ALS. No FUS mutations were found in 133 patients with sporadic disease. The authors sequenced only the C-terminal region of the gene encompassing exons 13 to 15. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20660363" 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="#38" class="mim-tip-reference" title="Yan, J., Deng, H.-X., Siddique, N., Fecto, F., Chen, W., Yang, Y., Liu, E., Donkervoort, S., Zheng, J. G., Shi, Y., Ahmeti, K. B., Brooks, B., Engel, W. K., Siddique, T. <strong>Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia.</strong> Neurology 75: 807-814, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20668259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20668259</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20668259[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181f07e0c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20668259">Yan et al. (2010)</a> identified 16 heterozygous FUS mutations, including 11 novel mutations (see, e.g., G206S; <a href="#0010">137070.0010</a>), in 25 (5.6%) of 476 patients with familial ALS who did not have mutations in the SOD1 (<a href="/entry/147450">147450</a>) or TARDBP (<a href="/entry/605078">605078</a>) genes. All exons in the FUS gene were screened, but 12 of the 16 mutations were found in exons 14 and 15. No mutations were found in 41 patients with sporadic ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20668259" 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="Deng, H.-X., Zhai, H., Bigio, E. H., Yan, J., Fecto, F., Ajroud, K., Mishra, M., Ajroud-Driss, S., Heller, S., Sufit, R., Siddique, N., Mugnaini, E., Siddique, T. <strong>FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis.</strong> Ann. Neurol. 67: 739-748, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20517935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20517935</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20517935[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.22051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20517935">Deng et al. (2010)</a> studied postmortem spinal cord sections from 52 patients with sporadic ALS (SALS), 16 with familial ALS (FALS), 10 with ALS with dementia, and 11 with frontotemporal lobar degeneration (FTLD). Only 1 of the patients had an FUS mutation, and 4 had an SOD1 (<a href="/entry/147450">147450</a>) mutation. FUS-immunoreactivity was found in some of the surviving spinal motor neurons of all 52 patients with SALS, in 12 SOD1-negative FALS patients, and in 10 ALS with dementia patients. None of the 4 patients with SOD1 mutations had FUS-immunoreactive inclusions. The FUS-positive inclusions were skein-like and were found in the cytoplasm of large anterior horn neurons and their neurites. FUS-positive inclusions colocalized with ubiquitin (UBB; <a href="/entry/191339">191339</a>) and p62 (<a href="/entry/601530">601530</a>), as well as with TDP43 (<a href="/entry/605078">605078</a>). Nine patients with FTLD had rare FUS-, UBB-, and TDP43-positive inclusions. Two patients with atypical FTLD also had FUS-positive inclusions, but these inclusions were negative for TDP43. The findings suggested that posttranslational modification of FUS is involved in a wider range of neurodegenerative disorders than FUS-related ALS, and also suggested that SOD1-related ALS has a distinct pathogenic pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20517935" 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>Ataxin-2 (ATXN2; <a href="/entry/601517">601517</a>) is a polyglutamine protein that normally contains 22 repeats, but it contains 34 or more repeats in spinocerebellar ataxia-2 (SCA2; <a href="/entry/183090">183090</a>). Intermediate repeat lengths (27 to 33) are associated with increased risk of ALS (see ALS13; <a href="/entry/183090">183090</a>). <a href="#10" class="mim-tip-reference" title="Farg, M. A., Soo, K. Y., Warraich, S. T., Sundaramoorthy, V., Blair, I. P., Atkin, J. D. <strong>Ataxin-2 interacts with FUS and intermediate-length polyglutamine expansions enhance FUS-related pathology in amyotrophic lateral sclerosis.</strong> Hum. Molec. Genet. 22: 717-728, 2013. Note: Erratum: Hum. Molec. Genet. 29: 703-704, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23172909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23172909</a>] [<a href="https://doi.org/10.1093/hmg/dds479" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23172909">Farg et al. (2013)</a> found that ataxin-2 with 31 repeats (Q31) interacted with wildtype FUS and, more strongly, with FUS containing the R521C or arg521-to-his (R521H; <a href="#0005">137070.0005</a>) mutations. The interactions were independent of RNA. Western blot analysis revealed at least 3 low molecular mass FUS species (about 40 to 60 kD) in ALS patient tissues that did not coprecipitate with ataxin-2. Ataxin-2 colocalized with FUS in sporadic and FUS-linked familial ALS patient motor neurons, coprecipitated with FUS in ALS spinal cord lysates, and colocalized with FUS in the ER and Golgi compartments in a mouse neuronal cell line. Ataxin-2 Q31 exacerbated the cellular phenotype of mutant FUS, increasing translocation of FUS from the nucleus to the cytoplasm, markers of ER stress, and Golgi fragmentation. Neither FUS with the R521H mutation nor ataxin-2 Q31 alone induced apoptosis in transfected mouse neuronal cells, but coexpression of both induced markers of early apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23172909" 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="#34" class="mim-tip-reference" title="Vance, C., Scotter, E. L., Nishimura, A. L., Troakes, C., Mitchell, J. C., Kathe, C., Urwin, H., Manser, C., Miller, C. C., Hortobagyi, T., Dragunow, M., Rogelj, B., Shaw, C. E. <strong>ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within cytoplasmic stress granules.</strong> Hum. Molec. Genet. 22: 2676-2688, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23474818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23474818</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23474818[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/ddt117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23474818">Vance et al. (2013)</a> found that FUS proteins with ALS-linked mutations in the C-terminal nuclear localization signal accumulated in the cytoplasm of transfected cells and patient fibroblasts. Mutant, but not wildtype, FUS localized to cytoplasmic stress granules and interacted with the stress granule protein PABP (PABPC1; <a href="/entry/604679">604679</a>) in an RNA-dependent manner. Addition of the wildtype C-terminal nuclear localization signal to full-length mutant FUS restored predominant nuclear localization. Sodium arsenite-induced oxidative stress caused formation of PABP-positive stress granules, with sequestration of mutant, but not wildtype, FUS to stress granules. Mutant FUS also interacted with wildtype FUS in an RNA-independent manner, and this interaction resulted in mislocalization of the wildtype protein to stress granules. <a href="#34" class="mim-tip-reference" title="Vance, C., Scotter, E. L., Nishimura, A. L., Troakes, C., Mitchell, J. C., Kathe, C., Urwin, H., Manser, C., Miller, C. C., Hortobagyi, T., Dragunow, M., Rogelj, B., Shaw, C. E. <strong>ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within cytoplasmic stress granules.</strong> Hum. Molec. Genet. 22: 2676-2688, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23474818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23474818</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23474818[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/ddt117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23474818">Vance et al. (2013)</a> hypothesized that FUS may function in shuttling nuclear RNA to cytoplasmic stress granules for degradation and that elevated cytoplasmic mutant FUS interferes with RNA processing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23474818" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a bioinformatics approach combined with in vitro cellular expression studies, <a href="#26" class="mim-tip-reference" title="Rebelo, A. P., Abrams, A. J., Cottenie, E., Horga, A., Gonzalez, M., Bis, D. M., Sanchez-Mejias, A., Pinto, M., Buglo, E., Markel, K., Prince, J., Laura, M., and 10 others. <strong>Cryptic amyloidogenic elements in the 3-prime UTRs of neurofilament genes trigger axonal neuropathy.</strong> Am. J. Hum. Genet. 98: 597-614, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27040688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27040688</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27040688[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.02.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27040688">Rebelo et al. (2016)</a> identified FUS as a gene with the potential to cause abnormal and toxic protein aggregations as a result of a stop-loss mutation, i.e., a mutation that extends the 3-prime translation frame beyond the normal stop codon, resulting in the addition of cryptic amyloidogenic elements (CAE). Although this type of mutation had not yet been reported in FUS, neuronal cells expressing such frameshift FUS mutations showed prominent toxic protein aggregations in the cytoplasm and in neuronal projections, indicating that they would be pathogenic and thus could likely result in neurologic disorders. A similar gain-of-function mechanism was observed for frameshift mutations in the neurofilament genes NEFH (<a href="/entry/162230">162230</a>) and NEFL (<a href="/entry/162280">162280</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27040688" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Hereditary Essential Tremor 4</em></strong></p><p>
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In affected members of a large family with hereditary essential tremor-4 (ETM4; <a href="/entry/614782">614782</a>), <a href="#18" class="mim-tip-reference" title="Merner, N. D., Girard, S. L., Catoire, H., Bourassa, C. V., Belzil, V. V., Riviere, J. B., Hince, P., Levert, A., Dionne-Laporte, A., Spiegelman, D., Noreau, A., Diab, S., and 11 others. <strong>Exome sequencing identifies FUS mutations as a cause of essential tremor.</strong> Am. J. Hum. Genet. 91: 313-319, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22863194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22863194</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22863194[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.07.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22863194">Merner et al. (2012)</a> identified a heterozygous mutation in the FUS gene (Q290X; <a href="#0011">137070.0011</a>) that segregated with the disorder in all patients who were determined to be 'definitely' or 'probably' affected. However, only 54% of those who were 'possibly' affected carried the mutation, and 1 unaffected individual who was 24 years old carried the mutation. The mutation was found by exome sequencing. The Q290X mutation was demonstrated to result in nonsense-mediated mRNA decay. Sequencing the FUS gene in 270 additional probands with essential tremor found that 3 patients had 2 different heterozygous mutations (R216C, <a href="#0007">137070.0007</a> and P431L, <a href="#0012">137070.0012</a>). Two of these patients had a family history of the disorder, but family members were not available for study. ETM4 patient lymphoblastoid cells with the FUS mutations showed significantly lower overall expression of mutant FUS mRNA compared to cells from patients with ALS6 due to FUS mutations. In addition, ETM4 cells with the mutations showed a significant increase in FUS mRNA expression after treatment with the translation inhibitor puromycin, which was not seen with ALS6 FUS mutations. These findings indicated that truncating FUS mutations in ETM4 are associated with nonsense-mediated mRNA decay, whereas mutant FUS from ALS6 cells appear to escape nonsense-mediated mRNA decay. Thus, ETM4 may be due to loss of FUS function, whereas ALS6 may result from a toxic gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22863194" 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>The FUS protein contains an RNA-recognition motif and is a component of nuclear riboprotein complexes. FUS resembles a transcription factor in that it binds DNA, contributes a transcriptional activation domain to the FUS/ERG oncoprotein, and interacts with several transcription factors in vitro. By examining the consequences of Fus disruption in mice, <a href="#12" class="mim-tip-reference" title="Hicks, G. G., Singh, N., Nashabi, A., Mai, S., Bozek, G., Klewes, L., Arapovic, D., White, E. K., Koury, M. J., Oltz, E. M., Van Kaer, L., Ruley, H. E. <strong>Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death.</strong> Nature Genet. 24: 175-179, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10655065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10655065</a>] [<a href="https://doi.org/10.1038/72842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10655065">Hicks et al. (2000)</a> found that Fus was essential for viability of neonatal animals, influenced lymphocyte development in a non-cell-intrinsic manner, had an intrinsic role in the proliferative responses of B cells to specific mitogenic stimuli, and was required for the maintenance of genomic stability. The involvement of a nuclear riboprotein in these processes in vivo indicated that Fus is important in genome maintenance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10655065" 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="#30" class="mim-tip-reference" title="Shelkovnikova, T. A., Peters, O. M., Deykin, A. V., Connor-Robson, N., Robinson, H., Ustyugov, A. A., Bachurin, S. O., Ermolkevich, T. G., Goldman, I. L., Sadchikova, E. R., Kovrazhkina, E., A., Skvortsova, V. I., Ling, S.-C., Da Cruz, S., Parone, P. A., Buchman, V. L., Ninkina, N. N. <strong>Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice.</strong> J. Biol. Chem. 288: 25266-25274, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23867462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23867462</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23867462[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.M113.492017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23867462">Shelkovnikova et al. (2013)</a> generated transgenic mice expressing a truncated FUS protein (FUS1-359) that was predominantly cytoplasmic, highly aggregate-prone, and lacking a region responsible for RNA recognition and binding. Hemizygous mutant mice were indistinguishable from wildtype controls until age 2.5 to 4.5 months when they abruptly developed severe progressive motor dysfunction and died. Immunohistochemical analysis of the central nervous system of the mutant mice demonstrated that the truncated protein had rapidly aggregated and was able to seed aggregation of wildtype FUS protein. Additional analyses showed that the aggregation of FUS was sufficient to recapitulate the motor pathology of ALS in the mutant mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23867462" 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="#31" class="mim-tip-reference" title="Shiihashi, G., Ito, D., Yagi, T., Nihei, Y., Ebine, T., Suzuki, N. <strong>Mislocated FUS is sufficient for gain-of-toxic-function amyotrophic lateral sclerosis phenotypes in mice.</strong> Brain 139: 2380-2394, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27368346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27368346</a>] [<a href="https://doi.org/10.1093/brain/aww161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27368346">Shiihashi et al. (2016)</a> created transgenic mice expressing neuronal-targeted human FUS that lacked its C-terminal nuclear localization signal (delta-NLS-FUS). Transgenic mice were born at the expected mendelian ratio and appeared normal in weight and behavior at birth. Delta-NLS-FUS was expressed exclusively in the cytoplasm in cortex and pyramidal tract of transgenic animals and accumulated in ubiquitin-positive inclusions. Expression of delta-NLS-FUS did not alter the amount or nuclear localization of endogenous mouse Fus. At 48 weeks, delta-NLS-FUS mice developed an abnormal hindlimb reflex and progressive motor weakness, prior to noticeable neuronal loss, which occurred at approximately 1 year. Cytoplasmic delta-NLS-FUS progressively reduced the number of nuclear Gemini of coiled bodies (GEMs) in cortical neurons, but not in spinal motor neurons. RNA sequence analysis revealed that delta-NLS-FUS altered expression of hundreds of genes, notably those regulating dynein-associated molecules and endoplasmic reticulum stress. Coexpression of human TDP43 (TARDBP; <a href="/entry/605078">605078</a>) did not affect total neuronal content of TDP43 (exogenous plus endogenous), but exacerbated the phenotype of delta-NLS-FUS transgenic mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27368346" 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="#17" class="mim-tip-reference" title="Lopez-Erauskin, J., Tadokoro, T., Baugyn, M. W., Myers, B., McAlonis-Downes, M., Chillon-Marinas, C., Asiaban, J. N., Artates, J., Bui, A. T., Vetto, A. P., Lee, S. K., Le, A. V., and 16 others. <strong>ALS/FTD-linked mutation in FUS suppresses intra-axonal protein synthesis and drives disease without nuclear loss-of-function of FUS.</strong> Neuron 100: 816-830, 2018. Note: Erratum: Neuron 106: 354 only, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30344044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30344044</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30344044[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2018.09.044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30344044">Lopez-Erauskin et al. (2018)</a> generated FUS mice expressing full-length human FUS and found that when expressed at near endogenous mouse FUS levels, both wildtype and ALS-causing and frontotemporal dementia (FTD)-causing mutations (R521C and R521H) complemented the essential functions of mouse FUS. However, replacement of mouse FUS with only mutant human FUS resulted in stress-mediated induction of chaperones, decreased expression of ion channels and transporters essential for synaptic function, and reduced synaptic activity without loss of nuclear FUS or its cytoplasmic aggregation. The integrated stress response induced in mutant FUS impaired local protein synthesis within axons. ALS/FTD-linked FUS mutant mice developed progressive neurodegeneration, with age-dependent motor deficits and cognitive and memory deficits accompanied by astrogliosis, microgliosis, and loss of synapses in the hippocampus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30344044" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909667 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909667;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/rs121909667?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=rs121909667" 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=rs121909667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 4 affected members of a consanguineous family with amyotrophic lateral sclerosis-6 (ALS6; <a href="/entry/608030">608030</a>), <a href="#14" class="mim-tip-reference" title="Kwiatkowski, T. J., Jr., Bosco, D. A., LeClerc, A.L., Tamrazian, E., Vanderburg, C. R., Russ, C., Davis, A., Gilchrist, J., Kasarskis, E. J., Munsat, T., Valdmanis, P., Rouleau, G. A., and 14 others. <strong>Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.</strong> Science 323: 1205-1208, 2009. Note: Erratum: Science 324: 465 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251627</a>] [<a href="https://doi.org/10.1126/science.1166066" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251627">Kwiatkowski et al. (2009)</a> identified a homozygous 1551C-G transversion in exon 15 of the FUS gene, resulting in a his517-to-gln (H517Q) substitution. The family originated from Cape Verde, a small island off the western coast of Africa. Three asymptomatic family members were also homozygous for the mutation, but all were younger than the mean age at disease onset of 45 years. The mutation was not detected in 1,446 control DNA samples from North America; 1 heterozygote was observed in 132 chromosomes from Cape Verde. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19251627" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909668 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909668;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/rs121909668?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=rs121909668" 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=rs121909668" 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=RCV000017609 OR RCV000703284 OR RCV002472932 OR RCV003421921" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017609, RCV000703284, RCV002472932, RCV003421921" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017609...</a>
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<p>In affected members of a family with amyotrophic lateral sclerosis (ALS6; <a href="/entry/608030">608030</a>) (<a href="#29" class="mim-tip-reference" title="Sapp, P. C., Hosler, B. A., McKenna-Yasek, D., Chin, W., Gann, A., Genise, H., Gorenstein, J., Huang, M., Sailer, W., Scheffler, M., Valesky, M., Haines, J. L., Pericak-Vance, M., Siddique, T., Horvitz, H. R., Brown, R. H., Jr. <strong>Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis.</strong> Am. J. Hum. Genet. 73: 397-403, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12858291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12858291</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12858291[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/10.1086/377158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12858291">Sapp et al., 2003</a>), <a href="#14" class="mim-tip-reference" title="Kwiatkowski, T. J., Jr., Bosco, D. A., LeClerc, A.L., Tamrazian, E., Vanderburg, C. R., Russ, C., Davis, A., Gilchrist, J., Kasarskis, E. J., Munsat, T., Valdmanis, P., Rouleau, G. A., and 14 others. <strong>Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.</strong> Science 323: 1205-1208, 2009. Note: Erratum: Science 324: 465 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251627</a>] [<a href="https://doi.org/10.1126/science.1166066" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251627">Kwiatkowski et al. (2009)</a> identified a heterozygous 1561C-G transversion in exon 15 of the FUS gene, resulting in an arg521-to-gly (R521G) substitution. Inheritance was autosomal dominant with incomplete penetrance, and the mean age at onset was 39.6 years. Affected individuals from 2 additional unrelated ALS6 families also had the heterozygous R521G mutation. The mutation was not found in 1,446 control DNA samples. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19251627+12858291" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909669 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909669;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=rs121909669" 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=rs121909669" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family with amyotrophic lateral sclerosis (ALS6; <a href="/entry/608030">608030</a>), <a href="#14" class="mim-tip-reference" title="Kwiatkowski, T. J., Jr., Bosco, D. A., LeClerc, A.L., Tamrazian, E., Vanderburg, C. R., Russ, C., Davis, A., Gilchrist, J., Kasarskis, E. J., Munsat, T., Valdmanis, P., Rouleau, G. A., and 14 others. <strong>Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.</strong> Science 323: 1205-1208, 2009. Note: Erratum: Science 324: 465 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251627</a>] [<a href="https://doi.org/10.1126/science.1166066" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251627">Kwiatkowski et al. (2009)</a> identified a heterozygous 1553G-A transition in exon 15 of the FUS gene, resulting in an arg518-to-lys (R518K) substitution. Inheritance was autosomal dominant, and the mean age at onset was 40.3 years. The mutation was not found in 1,446 control DNA samples. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19251627" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 AMYOTROPHIC LATERAL SCLEROSIS 6 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909668 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909668;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/rs121909668?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=rs121909668" 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=rs121909668" 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=RCV000017611 OR RCV001701569 OR RCV001851894 OR RCV004745160" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017611, RCV001701569, RCV001851894, RCV004745160" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017611...</a>
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<p>In affected members of 3 unrelated families with amyotrophic lateral sclerosis (ALS6; <a href="/entry/608030">608030</a>), <a href="#14" class="mim-tip-reference" title="Kwiatkowski, T. J., Jr., Bosco, D. A., LeClerc, A.L., Tamrazian, E., Vanderburg, C. R., Russ, C., Davis, A., Gilchrist, J., Kasarskis, E. J., Munsat, T., Valdmanis, P., Rouleau, G. A., and 14 others. <strong>Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.</strong> Science 323: 1205-1208, 2009. Note: Erratum: Science 324: 465 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251627</a>] [<a href="https://doi.org/10.1126/science.1166066" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251627">Kwiatkowski et al. (2009)</a> identified a heterozygous 1561C-T transition in exon 15 of the FUS gene, resulting in an arg521-to-cys (R521C) in the C-terminal domain. The mutation was not found in 1,446 control DNA samples. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19251627" 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="#33" class="mim-tip-reference" title="Vance, C., Rogelj, B., Hortobagyi, T., De Vos, K. J., Nishimura, A. L., Sreedharan, J., Hu, X., Smith, B., Ruddy, D., Wright, P., Ganesalingam, J., Williams, K. L., and 10 others. <strong>Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6.</strong> Science 323: 1208-1211, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19251628[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1165942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251628">Vance et al. (2009)</a> identified a heterozygous R521C mutation in 6 affected members of a British family with ALS6 (<a href="#28" class="mim-tip-reference" title="Ruddy, D. M., Parton, M. J., Al-Chalabi, A., Lewis, C. M., Vance, C., Smith, B. N., Leigh, P. N., Powell, J. F., Siddique, T., Meyjes, E. P., Baas, F., De Jong, V., Shaw, C. E. <strong>Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q.</strong> Am. J. Hum. Genet. 73: 390-396, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12840784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12840784</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12840784[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/10.1086/377157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12840784">Ruddy et al., 2003</a>) and in 3 affected members of an additional family with ALS and in 3 index ALS cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12840784+19251628" 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="Corrado, L., Del Bo, R., Castellotti, B., Ratti, A., Cereda, C., Penco, S., Soraru, G., Carlomagno, Y., Ghezzi, S., Pensato, V., Colombrita, C., Gagliardi, S., and 10 others. <strong>Mutations of FUS gene in sporadic amyotrophic lateral sclerosis.</strong> J. Med. Genet. 47: 190-194, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19861302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19861302</a>] [<a href="https://doi.org/10.1136/jmg.2009.071027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19861302">Corrado et al. (2010)</a> identified a heterozygous R521C mutation in 2 unrelated Italian patients with ALS6. One had a family history of the disorder, and the other had sporadic disease. Onset occurred at age 34 and 54 years, respectively, and both had an unusual phenotype with proximal, mostly symmetric upper limb weakness with neck and axial involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19861302" 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="#19" 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 heterozygosity for the R521C mutation in 3 of 162 French probands with familial ALS. One patient was also heterozygous for a mutation in the ANG gene (K17I; <a href="/entry/105850#0002">105850.0002</a>), which causes ALS9 (<a href="/entry/611895">611895</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'})"><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="#38" class="mim-tip-reference" title="Yan, J., Deng, H.-X., Siddique, N., Fecto, F., Chen, W., Yang, Y., Liu, E., Donkervoort, S., Zheng, J. G., Shi, Y., Ahmeti, K. B., Brooks, B., Engel, W. K., Siddique, T. <strong>Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia.</strong> Neurology 75: 807-814, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20668259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20668259</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20668259[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181f07e0c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20668259">Yan et al. (2010)</a> identified heterozygosity for the R521C mutation in 6 families with ALS6: 4 were Caucasian, 1 was African American, and 1 was Chinese. Five families had classic ALS6. The proband in the remaining family had ALS, her brother had parkinsonism and dementia, and her mother and sister had dementia. These features expanded the phenotype associated with FUS mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20668259" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of a family with autosomal dominant amyotrophic lateral sclerosis (ALS6; <a href="/entry/608030">608030</a>), <a href="#14" class="mim-tip-reference" title="Kwiatkowski, T. J., Jr., Bosco, D. A., LeClerc, A.L., Tamrazian, E., Vanderburg, C. R., Russ, C., Davis, A., Gilchrist, J., Kasarskis, E. J., Munsat, T., Valdmanis, P., Rouleau, G. A., and 14 others. <strong>Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.</strong> Science 323: 1205-1208, 2009. Note: Erratum: Science 324: 465 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251627</a>] [<a href="https://doi.org/10.1126/science.1166066" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251627">Kwiatkowski et al. (2009)</a> identified a heterozygous 1562G-A transition in exon 15 of the FUS gene, resulting in an arg521-to-his (R521H) substitution. The mutation was not found in 1,446 control DNA samples. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19251627" 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="#33" class="mim-tip-reference" title="Vance, C., Rogelj, B., Hortobagyi, T., De Vos, K. J., Nishimura, A. L., Sreedharan, J., Hu, X., Smith, B., Ruddy, D., Wright, P., Ganesalingam, J., Williams, K. L., and 10 others. <strong>Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6.</strong> Science 323: 1208-1211, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19251628[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1165942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251628">Vance et al. (2009)</a> identified a heterozygous R521H substitution in affected members of 2 families with ALS6 and 1 index case. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19251628" 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">rs267606831 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606831;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=rs267606831" 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=rs267606831" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 unrelated Italian patients with sporadic amyotrophic lateral sclerosis (ALS6; <a href="/entry/608030">608030</a>), <a href="#5" class="mim-tip-reference" title="Corrado, L., Del Bo, R., Castellotti, B., Ratti, A., Cereda, C., Penco, S., Soraru, G., Carlomagno, Y., Ghezzi, S., Pensato, V., Colombrita, C., Gagliardi, S., and 10 others. <strong>Mutations of FUS gene in sporadic amyotrophic lateral sclerosis.</strong> J. Med. Genet. 47: 190-194, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19861302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19861302</a>] [<a href="https://doi.org/10.1136/jmg.2009.071027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19861302">Corrado et al. (2010)</a> identified a heterozygous 1520G-A transition in exon 14 of the FUS gene, resulting in a gly507-to-asp (G507D) substitution in a conserved residue. The mutation was not found in 500 healthy controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19861302" 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="#11" class="mim-tip-reference" title="Hewitt, C., Kirby, J., Highley, J. R., Hartley, J. A., Hibberd, R., Hollinger, H. C., Williams, T. L., Ince, P. G., McDermott, C. J., Shaw, P. J. <strong>Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis.</strong> Arch. Neurol. 67: 455-461, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20385912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20385912</a>] [<a href="https://doi.org/10.1001/archneurol.2010.52" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20385912">Hewitt et al. (2010)</a> identified a heterozygous G507D mutation in a U.K. man with predominantly lower motor neuron ALS involving both the lower and upper limbs. He had no family history of neurologic disease, had onset at age 69 years, and died of respiratory failure 42 months after symptom onset. Postmortem examination showed marked loss of lower motor neurons at all spinal levels and neuronal and glial cytoplasmic inclusions, which stained for FUS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20385912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267606832 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606832;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/rs267606832?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=rs267606832" 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=rs267606832" 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=RCV000017614 OR RCV000030719 OR RCV001588814 OR RCV002247351 OR RCV002513082 OR RCV004745162" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017614, RCV000030719, RCV001588814, RCV002247351, RCV002513082, RCV004745162" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017614...</a>
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<p>In 1 of 1,009 Italian patients with amyotrophic lateral sclerosis (ALS6; <a href="/entry/608030">608030</a>), <a href="#5" class="mim-tip-reference" title="Corrado, L., Del Bo, R., Castellotti, B., Ratti, A., Cereda, C., Penco, S., Soraru, G., Carlomagno, Y., Ghezzi, S., Pensato, V., Colombrita, C., Gagliardi, S., and 10 others. <strong>Mutations of FUS gene in sporadic amyotrophic lateral sclerosis.</strong> J. Med. Genet. 47: 190-194, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19861302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19861302</a>] [<a href="https://doi.org/10.1136/jmg.2009.071027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19861302">Corrado et al. (2010)</a> identified a heterozygous 646C-T transition in exon 6 of the FUS gene, resulting in an arg216-to-cys (R216C) substitution in a conserved residue. The mutation was not found in 793 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19861302" 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 2 of 270 unrelated patients with hereditary essential tremor-4 (ETM4; <a href="/entry/614782">614782</a>), <a href="#18" class="mim-tip-reference" title="Merner, N. D., Girard, S. L., Catoire, H., Bourassa, C. V., Belzil, V. V., Riviere, J. B., Hince, P., Levert, A., Dionne-Laporte, A., Spiegelman, D., Noreau, A., Diab, S., and 11 others. <strong>Exome sequencing identifies FUS mutations as a cause of essential tremor.</strong> Am. J. Hum. Genet. 91: 313-319, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22863194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22863194</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22863194[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.07.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22863194">Merner et al. (2012)</a> identified a heterozygous R216C substitution at a highly conserved residue in the glycine-rich domain. The mutation was found in 1 (0.1%) of 900 control alleles. One of the patients had a family history of the disorder, but family members were not available for study. The mutation disrupts a CpG site, which may cause an epigenetic effect on gene expression through changes in methylation. ETM4 patient lymphoblastoid cells showed significantly lower overall expression of mutant FUS mRNA than did cells from patients with ALS due to FUS mutations. In addition, ETM4 cells with the R216C mutation showed a significant increase in FUS mRNA expression after treatment with the translation inhibitor puromycin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22863194" 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">rs267606833 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606833;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=rs267606833" 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=rs267606833" 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=RCV000017615 OR RCV001362689" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017615, RCV001362689" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017615...</a>
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<p>In 3 U.K. patients, including 2 sibs, with amyotrophic lateral sclerosis (ALS6; <a href="/entry/608030">608030</a>), <a href="#11" class="mim-tip-reference" title="Hewitt, C., Kirby, J., Highley, J. R., Hartley, J. A., Hibberd, R., Hollinger, H. C., Williams, T. L., Ince, P. G., McDermott, C. J., Shaw, P. J. <strong>Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis.</strong> Arch. Neurol. 67: 455-461, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20385912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20385912</a>] [<a href="https://doi.org/10.1001/archneurol.2010.52" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20385912">Hewitt et al. (2010)</a> identified a heterozygous 1570A-T transversion in exon 15 of the FUS gene, resulting in an arg524-to-trp (R524W) substitution. The mutation was not found in 293 controls. One of the patients had onset of a progressive muscular atrophy variant of motor neuron disease with upper limb onset at the age of 61 years. His brother presented with a similar pattern of disease at age 58, but DNA was not available. Postmortem examination of the first patient showed marked depletion of lower motor neurons with glial cytoplasmic and nuclear inclusions that stained for p62 (SQSTM1; <a href="/entry/601530">601530</a>). There was FUS staining predominantly in the nucleus of neurons and glia, with some lower motor neurons showing strong cytoplasmic FUS expression. An affected brother and sister with the R524W mutation had classic limb-onset ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20385912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906627 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906627;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/rs387906627?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=rs387906627" 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=rs387906627" 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=RCV000022556 OR RCV002247377 OR RCV003764624" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022556, RCV002247377, RCV003764624" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022556...</a>
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<p>In 3 affected members of a German family with amyotrophic lateral sclerosis (ALS6; <a href="/entry/608030">608030</a>), <a href="#35" class="mim-tip-reference" title="Waibel, S., Neumann, M., Rabe, M., Meyer, T., Ludolph, A. C. <strong>Novel missense and truncating mutations in FUL/TLS in familial ALS.</strong> Neurology 75: 815-817, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20660363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20660363</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181f07e26" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20660363">Waibel et al. (2010)</a> identified a heterozygous 1483C-T transition in exon 14 of the FUS gene, resulting in an arg495-to-ter (R495X) substitution predicted to produced a truncated protein lacking the nuclear localization sequence. The age at onset ranged from 31 to 36 years, with rapid disease progression leading to death 12 to 18 months later. All presented with bulbar signs and symptoms and had predominantly lower motor signs. None had dementia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20660363" 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="#38" class="mim-tip-reference" title="Yan, J., Deng, H.-X., Siddique, N., Fecto, F., Chen, W., Yang, Y., Liu, E., Donkervoort, S., Zheng, J. G., Shi, Y., Ahmeti, K. B., Brooks, B., Engel, W. K., Siddique, T. <strong>Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia.</strong> Neurology 75: 807-814, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20668259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20668259</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20668259[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181f07e0c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20668259">Yan et al. (2010)</a> identified heterozygosity for the R495X mutation in a Caucasian family with ALS6. There was wide phenotypic variability: the age at onset ranged from 24 to 44 years in 4 mutation carriers, and 2 mutation carriers were unaffected at age 57 and 61 years, respectively. One mutation carrier had onset at age 14 years, and postmortem analysis was consistent with Fazio-Londe disease (<a href="/entry/211500">211500</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20668259" 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="#4" class="mim-tip-reference" title="Bosco, D. A., Lemay, N., Ko, H. K., Zhou, H., Burke, C., Kwiatkowski, T. J., Jr., Sapp, P., McKenna-Yasek, D., Brown, R. H., Jr., Hayward, L. J. <strong>Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules.</strong> Hum. Molec. Genet. 19: 4160-4175, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20699327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20699327</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20699327[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/ddq335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20699327">Bosco et al. (2010)</a> reported a 5-generation family with 8 affected members with early-onset ALS caused by the R495X mutation, which led to a relatively severe ALS clinical phenotype compared with FUS missense mutations. Expression of R495X FUS, which abrogates a putative nuclear localization signal at the C terminus of FUS, in HEK-293 cells and in the zebrafish spinal cord caused a striking cytoplasmic accumulation of the protein to a greater extent than that observed for recessive (H517Q; <a href="#0001">137070.0001</a>) and dominant (R521G; <a href="#0002">137070.0002</a>) missense mutants. In response to oxidative stress or heat-shock conditions in cultures and in vivo, the ALS-linked FUS mutants, but not wildtype FUS, assembled into perinuclear stress granules in proportion to their cytoplasmic expression levels. The authors proposed a potential link between FUS mutations and cellular pathways involved in stress responses that may be relevant to altered motor neuron homeostasis in ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20699327" 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>.0010 AMYOTROPHIC LATERAL SCLEROSIS 6 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906628 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906628;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/rs387906628?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=rs387906628" 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=rs387906628" 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 family of South Korean origin with amyotrophic lateral sclerosis (ALS6; <a href="/entry/608030">608030</a>), <a href="#38" class="mim-tip-reference" title="Yan, J., Deng, H.-X., Siddique, N., Fecto, F., Chen, W., Yang, Y., Liu, E., Donkervoort, S., Zheng, J. G., Shi, Y., Ahmeti, K. B., Brooks, B., Engel, W. K., Siddique, T. <strong>Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia.</strong> Neurology 75: 807-814, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20668259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20668259</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20668259[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181f07e0c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20668259">Yan et al. (2010)</a> identified a heterozygous 616G-A transition in exon 6 of the FUS gene, resulting in a gly206-to-ser (G206S) substitution. The proband developed ALS at age 54 years, and his 2 brothers had behavior problems in their forties consistent with frontotemporal dementia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20668259" 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">rs387907274 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907274;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=rs387907274" 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=rs387907274" 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=RCV000030720" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030720" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030720</a>
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<p>In affected members of a large family with hereditary essential tremor-4 (ETM4; <a href="/entry/614782">614782</a>), <a href="#18" class="mim-tip-reference" title="Merner, N. D., Girard, S. L., Catoire, H., Bourassa, C. V., Belzil, V. V., Riviere, J. B., Hince, P., Levert, A., Dionne-Laporte, A., Spiegelman, D., Noreau, A., Diab, S., and 11 others. <strong>Exome sequencing identifies FUS mutations as a cause of essential tremor.</strong> Am. J. Hum. Genet. 91: 313-319, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22863194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22863194</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22863194[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.07.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22863194">Merner et al. (2012)</a> identified a heterozygous 868C-T transition in exon 9 of the FUS gene, resulting in a gln290-to-ter (Q290X) substitution in the nuclear export signal motif. The mutation segregated with the disorder in all patients who were determined to be 'definitely' or 'probably' affected. However, only 54% of those who were 'possibly' affected carried the mutation, and 1 unaffected individual who was 24 years old also carried the mutation. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in 450 controls or in a large exome database. Studies of patient lymphoblastoid cells showed that the mutant mRNA was degraded by nonsense-mediated mRNA decay, resulting in haploinsufficiency. ETM4 patient lymphoblastoid cells showed significantly lower overall expression of mutant FUS mRNA than did cells from patients with ALS6 due to FUS mutations. None of the patients over the age of onset of amyotrophic lateral sclerosis had signs of that disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22863194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 TREMOR, HEREDITARY ESSENTIAL, 4</strong>
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FUS, PRO431LEU
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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> rs186547381 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs186547381;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/rs186547381?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=rs186547381" 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=rs186547381" 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=RCV000030718 OR RCV000711709 OR RCV000765290 OR RCV001847624 OR RCV002381274 OR RCV003407373 OR RCV003993752" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030718, RCV000711709, RCV000765290, RCV001847624, RCV002381274, RCV003407373, RCV003993752" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030718...</a>
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<p>In a patient with hereditary essential tremor-4 (ETM4; <a href="/entry/614782">614782</a>), <a href="#18" class="mim-tip-reference" title="Merner, N. D., Girard, S. L., Catoire, H., Bourassa, C. V., Belzil, V. V., Riviere, J. B., Hince, P., Levert, A., Dionne-Laporte, A., Spiegelman, D., Noreau, A., Diab, S., and 11 others. <strong>Exome sequencing identifies FUS mutations as a cause of essential tremor.</strong> Am. J. Hum. Genet. 91: 313-319, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22863194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22863194</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22863194[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.07.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22863194">Merner et al. (2012)</a> identified a heterozygous 1292C-T transition in exon 12 of the FUS gene, resulting in a pro431-to-leu (P431L) substitution at a highly conserved residue in the zinc finger domain. The patient had a family history of the disorder, but family members were not available for analysis. The mutation was not found in 450 controls. Although the mutation occurred in the last nucleotide of exon 12, no splicing abnormalities were detected. ETM4 patient lymphoblastoid cells showed significantly lower overall expression of mutant FUS mRNA than did cells from patients with ALS6 due to FUS mutations. In addition, ETM4 cells with the P431L mutation showed a significant increase in FUS mRNA expression after treatment with the translation inhibitor puromycin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22863194" 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/10.1006/geno.1996.0513" target="_blank">Full Text</a>]
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Baechtold, H., Kuroda, M., Sok, J., Ron, D., Lopez, B. S., Akhmedov, A. T.
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<strong>Human 75-kDa DNA-pairing protein is identical to the pro-oncoprotein TLS/FUS and is able to promote D-loop formation.</strong>
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[<a href="https://doi.org/10.1074/jbc.274.48.34337" target="_blank">Full Text</a>]
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Bejarano, P. A., Padhya, T. A., Smith, R., Blough, R., Devitt, J. J., Gluckman, J. L.
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<strong>Hyalinizing spindle cell tumor with giant rosettes--a soft tissue tumor with mesenchymal and neuroendocrine features: an immunohistochemical, ultrastructural, and cytogenetic analysis.</strong>
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[<a href="https://doi.org/10.5858/2000-124-1179-HSCTWG" target="_blank">Full Text</a>]
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Bosco, D. A., Lemay, N., Ko, H. K., Zhou, H., Burke, C., Kwiatkowski, T. J., Jr., Sapp, P., McKenna-Yasek, D., Brown, R. H., Jr., Hayward, L. J.
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<strong>Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules.</strong>
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Hum. Molec. Genet. 19: 4160-4175, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20699327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20699327</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20699327[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=20699327" 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/ddq335" target="_blank">Full Text</a>]
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Corrado, L., Del Bo, R., Castellotti, B., Ratti, A., Cereda, C., Penco, S., Soraru, G., Carlomagno, Y., Ghezzi, S., Pensato, V., Colombrita, C., Gagliardi, S., and 10 others.
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[<a href="https://doi.org/10.1136/jmg.2009.071027" target="_blank">Full Text</a>]
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Crozat, A., Aman, P., Mandahl, N., Ron, D.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8510758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8510758</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8510758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/363640a0" target="_blank">Full Text</a>]
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Deng, H.-X., Zhai, H., Bigio, E. H., Yan, J., Fecto, F., Ajroud, K., Mishra, M., Ajroud-Driss, S., Heller, S., Sufit, R., Siddique, N., Mugnaini, E., Siddique, T.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20517935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20517935</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20517935[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=20517935" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.22051" target="_blank">Full Text</a>]
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Doi, H., Okamura, K., Bauer, P. O., Furukawa, Y., Shimizu, H., Kurosawa, M., Machida, Y., Miyazaki, H., Mitsui, K., Kuroiwa, Y., Nukina, N.
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[<a href="https://doi.org/10.1074/jbc.M705306200" target="_blank">Full Text</a>]
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Eneroth, M., Mandahl, N., Heim, S., Willen, H., Rydholm, A., Alberts, K. A., Mitelman, F.
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<strong>Localization of the chromosomal breakpoints of the t(12;16) in liposarcoma to subbands 12q13.3 and 16p11.2.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2372777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2372777</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2372777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0165-4608(90)90222-v" target="_blank">Full Text</a>]
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Farg, M. A., Soo, K. Y., Warraich, S. T., Sundaramoorthy, V., Blair, I. P., Atkin, J. D.
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<strong>Ataxin-2 interacts with FUS and intermediate-length polyglutamine expansions enhance FUS-related pathology in amyotrophic lateral sclerosis.</strong>
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Hum. Molec. Genet. 22: 717-728, 2013. Note: Erratum: Hum. Molec. Genet. 29: 703-704, 2013.
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[<a href="https://doi.org/10.1093/hmg/dds479" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneurol.2010.52" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/72842" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1166066" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.22319" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M008304200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2018.09.044" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2012.07.002" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2010.077180" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27040688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27040688</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27040688[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=27040688" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2016.02.022" target="_blank">Full Text</a>]
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<a id="27" class="mim-anchor"></a>
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<a id="Reid2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Reid, R., de Silva, M. V. C., Paterson, L., Ryan, E., Fisher, C.
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<strong>Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes share a common t(7;16)(q34;p11) translocation.</strong>
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[<a href="https://doi.org/10.1097/00000478-200309000-00006" target="_blank">Full Text</a>]
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<a id="28" class="mim-anchor"></a>
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<a id="Ruddy2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ruddy, D. M., Parton, M. J., Al-Chalabi, A., Lewis, C. M., Vance, C., Smith, B. N., Leigh, P. N., Powell, J. F., Siddique, T., Meyjes, E. P., Baas, F., De Jong, V., Shaw, C. E.
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<strong>Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12840784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12840784</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12840784[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=12840784" 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/10.1086/377157" target="_blank">Full Text</a>]
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<a id="29" class="mim-anchor"></a>
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<a id="Sapp2003" class="mim-anchor"></a>
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<div class="">
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Sapp, P. C., Hosler, B. A., McKenna-Yasek, D., Chin, W., Gann, A., Genise, H., Gorenstein, J., Huang, M., Sailer, W., Scheffler, M., Valesky, M., Haines, J. L., Pericak-Vance, M., Siddique, T., Horvitz, H. R., Brown, R. H., Jr.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12858291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12858291</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12858291[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=12858291" 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/10.1086/377158" target="_blank">Full Text</a>]
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<a id="Shelkovnikova2013" class="mim-anchor"></a>
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<div class="">
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Shelkovnikova, T. A., Peters, O. M., Deykin, A. V., Connor-Robson, N., Robinson, H., Ustyugov, A. A., Bachurin, S. O., Ermolkevich, T. G., Goldman, I. L., Sadchikova, E. R., Kovrazhkina, E., A., Skvortsova, V. I., Ling, S.-C., Da Cruz, S., Parone, P. A., Buchman, V. L., Ninkina, N. N.
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<strong>Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23867462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23867462</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23867462[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=23867462" 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.M113.492017" target="_blank">Full Text</a>]
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<a id="Shiihashi2016" class="mim-anchor"></a>
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<div class="">
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<strong>Mislocated FUS is sufficient for gain-of-toxic-function amyotrophic lateral sclerosis phenotypes in mice.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27368346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27368346</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27368346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/aww161" target="_blank">Full Text</a>]
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<a id="Storlazzi2003" class="mim-anchor"></a>
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<strong>Fusion of the FUS and BBF2H7 genes in low grade fibromyxoid sarcoma.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915480</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915480" 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/ddg237" target="_blank">Full Text</a>]
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<a id="Vance2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vance, C., Rogelj, B., Hortobagyi, T., De Vos, K. J., Nishimura, A. L., Sreedharan, J., Hu, X., Smith, B., Ruddy, D., Wright, P., Ganesalingam, J., Williams, K. L., and 10 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19251628[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=19251628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1165942" target="_blank">Full Text</a>]
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<a id="Vance2013" class="mim-anchor"></a>
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<div class="">
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Vance, C., Scotter, E. L., Nishimura, A. L., Troakes, C., Mitchell, J. C., Kathe, C., Urwin, H., Manser, C., Miller, C. C., Hortobagyi, T., Dragunow, M., Rogelj, B., Shaw, C. E.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23474818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23474818</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23474818[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=23474818" 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/ddt117" target="_blank">Full Text</a>]
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<a id="Waibel2010" class="mim-anchor"></a>
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Waibel, S., Neumann, M., Rabe, M., Meyer, T., Ludolph, A. C.
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<strong>Novel missense and truncating mutations in FUL/TLS in familial ALS.</strong>
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[<a href="https://doi.org/10.1212/WNL.0b013e3181f07e26" target="_blank">Full Text</a>]
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<a id="36" class="mim-anchor"></a>
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<a id="Wang2008" class="mim-anchor"></a>
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Wang, X., Arai, S., Song, X., Reichart, D., Du, K., Pascual, G., Tempst, P., Rosenfeld, M. G., Glass, C. K., Kurokawa, R.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18509338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18509338</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18509338[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=18509338" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature06992" target="_blank">Full Text</a>]
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<div class="">
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Waters, B. L., Panagopoulos, I., Allen, E. F.
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<strong>Genetic characterization of angiomatoid fibrous histiocytoma identifies fusion of the FUS and ATF-1 genes induced by a chromosomal translocation involving bands 12q13 and 16p11.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11063792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11063792</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11063792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0165-4608(00)00237-5" target="_blank">Full Text</a>]
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<a id="Yan2010" class="mim-anchor"></a>
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Yan, J., Deng, H.-X., Siddique, N., Fecto, F., Chen, W., Yang, Y., Liu, E., Donkervoort, S., Zheng, J. G., Shi, Y., Ahmeti, K. B., Brooks, B., Engel, W. K., Siddique, T.
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<strong>Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia.</strong>
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Neurology 75: 807-814, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20668259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20668259</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20668259[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=20668259" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e3181f07e0c" target="_blank">Full Text</a>]
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<a id="Yang2000" class="mim-anchor"></a>
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Yang, L., Embree, L. J., Hickstein, D. D.
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<strong>TLS-ERG leukemia fusion protein inhibits RNA splicing mediated by serine-arginine proteins.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10779324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10779324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10779324[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=10779324" 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/10.1128/MCB.20.10.3345-3354.2000" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 02/11/2019
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Bao Lige - updated : 01/31/2019<br>Patricia A. Hartz - updated : 09/06/2017<br>George E. Tiller - updated : 06/23/2017<br>Cassandra L. Kniffin - updated : 4/27/2016<br>Patricia A. Hartz - updated : 9/10/2013<br>Cassandra L. Kniffin - updated : 8/6/2013<br>Patricia A. Hartz - updated : 7/18/2013<br>Cassandra L. Kniffin - updated : 3/18/2013<br>Cassandra L. Kniffin - updated : 9/11/2012<br>Cassandra L. Kniffin - updated : 12/15/2010<br>Cassandra L. Kniffin - updated : 9/28/2010<br>Cassandra L. Kniffin - updated : 8/16/2010<br>Cassandra L. Kniffin - updated : 6/22/2010<br>Cassandra L. Kniffin - updated : 9/1/2009<br>Ada Hamosh - updated : 8/29/2008<br>Victor A. McKusick - updated : 8/13/2004<br>Victor A. McKusick - updated : 1/12/2001<br>Paul J. Converse - updated : 7/14/2000<br>Paul J. Converse - updated : 7/7/2000<br>Patti M. Sherman - updated : 6/20/2000<br>Victor A. McKusick - updated : 1/28/2000<br>Moyra Smith - updated : 12/13/1996
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 6/21/1993
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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carol : 11/21/2024
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carol : 11/09/2022<br>carol : 01/27/2021<br>carol : 01/26/2021<br>carol : 08/28/2020<br>carol : 02/12/2019<br>carol : 02/11/2019<br>alopez : 01/31/2019<br>alopez : 09/06/2017<br>carol : 07/31/2017<br>alopez : 06/23/2017<br>carol : 04/28/2016<br>ckniffin : 4/27/2016<br>carol : 7/8/2015<br>mgross : 9/10/2013<br>carol : 8/9/2013<br>ckniffin : 8/6/2013<br>mgross : 7/18/2013<br>carol : 7/17/2013<br>ckniffin : 3/18/2013<br>carol : 9/11/2012<br>ckniffin : 9/11/2012<br>carol : 11/22/2011<br>ckniffin : 3/17/2011<br>carol : 1/19/2011<br>carol : 1/19/2011<br>wwang : 1/7/2011<br>ckniffin : 12/15/2010<br>wwang : 9/29/2010<br>ckniffin : 9/28/2010<br>wwang : 8/19/2010<br>ckniffin : 8/16/2010<br>ckniffin : 8/16/2010<br>wwang : 6/28/2010<br>ckniffin : 6/22/2010<br>terry : 12/16/2009<br>alopez : 9/9/2009<br>wwang : 9/1/2009<br>ckniffin : 9/1/2009<br>carol : 10/9/2008<br>alopez : 9/11/2008<br>terry : 8/29/2008<br>carol : 8/5/2008<br>wwang : 7/9/2008<br>ckniffin : 7/3/2008<br>tkritzer : 8/13/2004<br>tkritzer : 8/13/2004<br>carol : 5/20/2003<br>cwells : 1/18/2001<br>terry : 1/12/2001<br>mgross : 7/14/2000<br>mgross : 7/7/2000<br>mcapotos : 6/23/2000<br>psherman : 6/20/2000<br>alopez : 1/31/2000<br>terry : 1/28/2000<br>joanna : 6/10/1997<br>jamie : 12/17/1996<br>mark : 12/13/1996<br>jenny : 12/12/1996<br>mark : 12/9/1996<br>carol : 3/28/1994<br>carol : 6/28/1993<br>carol : 6/21/1993
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<span class="mim-font">
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<strong>*</strong> 137070
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<h3>
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FUS RNA-BINDING PROTEIN; FUS
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<em>Alternative titles; symbols</em>
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FUSED IN SARCOMA<br />
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FUSION, DERIVED FROM 12-16 TRANSLOCATION, MALIGNANT LIPOSARCOMA<br />
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TRANSLOCATED IN LIPOSARCOMA; TLS
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<span class="mim-font">
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Other entities represented in this entry:
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FUS/ATF1 FUSION GENE, INCLUDED
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FUS/CHOP FUSION GENE, INCLUDED<br />
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FUS/ERG FUSION GENE, INCLUDED<br />
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FUS/CREB3L2 FUSION GENE, INCLUDED
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: FUS</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1204334005;
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Cytogenetic location: 16p11.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:31,180,110-31,194,871 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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16p11.2
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<span class="mim-font">
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Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia
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<td>
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<span class="mim-font">
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608030
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<span class="mim-font">
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3
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Essential tremor, hereditary, 4
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<span class="mim-font">
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614782
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>FUS is a nucleoprotein that functions in DNA and RNA metabolism, including DNA repair, and the regulation of transcription, RNA splicing, and export to the cytoplasm. Translocation of the FUS transcriptional activation domain results in fusion proteins and has been implicated in tumorigenesis (summary by Vance et al., 2009). </p>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</h4>
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<span class="mim-text-font">
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<p>Rabbitts et al. (1993) identified the FUS gene as part of a fusion gene with the transcription factor gene CHOP (DDIT3; 126337) in tumor tissue derived from 2 patients with liposarcomas carrying t(12;16)(q13;p11) translocations. Nucleotide and derived protein sequences of the FUS gene were determined by isolating the gene from a cDNA library. The deduced 525-residue protein contains 3 glycine clusters and 6 potential N-linked glycosylation sites. Rabbitts et al. (1993) postulated that the fusion gene disrupted transcription. </p><p>Crozat et al. (1993) independently identified the FUS gene, which they termed 'TLS' for translocated in liposarcoma, in tissue tumor of human myxoid liposarcoma. The TLS gene was also fused with CHOP. The full-length TLS gene encodes a 526-amino acid protein. Western blot analysis detected TLS as a 68-kD band. They noted that a 1.9- to 2.0-kb transcript was detected in all cell lines and tissues examined. TLS was shown to be a nuclear RNA-binding protein with extensive sequence similarity to EWSR1 (133450), the product of a gene commonly translocated in Ewing sarcoma (612219). In the TLS/CHOP fusion gene, the RNA-binding domain of TLS was replaced by the DNA-binding and leucine zipper dimerization domain of CHOP. Crozat et al. (1993) suggested that the fusion protein caused a disruption in transcription. </p><p>Vance et al. (2013) reported that the full-length 526-amino acid FUS protein contains an N-terminal serine-, tyrosine-, glycine-, and glutamine-rich domain, followed by a glycine-rich region, an RNA recognition motif, and a zinc finger domain. Interspersed between these domains are 3 RGG repeat regions. Vance et al. (2013) determined that FUS also has a C-terminal proline-tyrosine nuclear localization signal. Epitope-tagged FUS localized predominantly to the nucleus of transfected human neuroblastoma cells. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Aman et al. (1996) defined the genomic structure of FUS and compared it with the structure of EWSR1. The FUS gene contains 15 exons located within 11 kb of genomic DNA. FUS exon 1 contains a 72-bp untranslated region and the translation initiation codon. Multiple glycine repeats occurred in a number of positions in the gene, and an RNP region was encoded by exons 9, 10 and 11. The exon/intron structures of FUS and EWSR1 showed extensive similarities in the RNP regions, suggesting that the 2 genes may have been derived from a common ancestor. The sequence upstream of the FUS transcription start site contained no TATA boxes but did contain stretches of C and G. </p><p>Morohoshi et al. (1998) determined that the FUS gene spans 12 kb. They noted that the conservation of the overall exon number and structure of RBP56 (601574), FUS, and EWSR1 indicates that they probably originated from the same ancestral gene. </p>
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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>Crozat et al. (1993) localized the FUS gene to chromosome 16p11 by analyzing the site of the breakpoint of translocation in Ewing sarcoma. The assignment was further narrowed to 16p11.2 by cytogenetic studies of Eneroth et al. (1990) and of Mrozek et al. (1993). </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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<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>Aman et al. (1996) found that the N-terminal ends of FUS and EWSR1 differed, but they shared extensive homology and were distinct from the N-terminal regions of other RNP-carrying proteins, suggesting that FUS and EWSR1 could be regarded as the first members of a new family of RNA-binding proteins. Several recognition sites for the transcription factors AP2 (107580), GCF (189901), and Sp1 (189906) were identified in FUS. Aman et al. (1996) stressed that the nature of the promoter regions of FUS and EWSR1 is important for understanding the control of the fusion genes involving FUS and EWSR1 in tumors. All tumor-specific translocations resulted in the formation of fusion genes with FUS or EWSR1 promoter regions and 5-prime coding regions linked to transcription factor genes. Thus, the transcriptional control of the fusion genes is most likely dominated by the FUS and EWS promoters. Aman et al. (1996) reported that exons 1 to 5 of FUS are invariably present in tumor-associated fusion proteins involving FUS. The tumor breakpoints in the EWSR1 and FUS genes are all localized in the same regions of the genes, upstream of the RNP encoding exons. FUS and EWSR1 were expressed in all tissues examined. </p><p>The leukemogenic potential of BCR (151410)/ABL (189980) oncoproteins depends on their tyrosine kinase activity and involves the activation of several downstream effectors, some of which are essential for cell transformation. Using electrophoretic mobility shift assays and Southwestern blot analyses with a double-stranded oligonucleotide containing a zinc finger consensus sequence, Perrotti et al. (1998) identified a 68-kD DNA-binding protein specifically induced by BCR/ABL. The peptide sequence of the affinity-purified protein was identical to that of the RNA-binding protein FUS. Binding activity of FUS required a functional BCR/ABL tyrosine kinase necessary to induce PRKCB2 (see 176970)-dependent FUS phosphorylation. Moreover, suppression of PRKCB2 activity in BCR/ABL-expressing cells by treatment with the PRKCB2 inhibitor CGP53353, or by expression of a dominant-negative PRKCB2, markedly impaired the ability of FUS to bind DNA. Suppression of FUS expression in myeloid precursor 32Dcl3 cells transfected with a FUS antisense construct was associated with upregulation of the granulocyte colony-stimulating factor receptor (GCSFR; 138971) and downregulation of interleukin-3 receptor beta-chain (IL3RB; 138981) expression, and accelerated GCSF (138970)-stimulated differentiation. Downregulation of FUS expression in BCR/ABL-expressing 32Dcl3 cells was associated with suppression of growth factor-independent colony formation, restoration of GCSF-induced granulocytic differentiation, and reduced tumorigenic potential in vivo. Perrotti et al. (1998) suggested that FUS might function as a regulator of BCR/ABL leukemogenesis, promoting growth factor independence and preventing differentiation via modulation of cytokine receptor expression. </p><p>By Western blot analysis, Yang et al. (2000) showed that the N-terminal domain of TLS binds to RNA polymerase II and that this binding was retained by the TLS/ERG (165080) fusion protein. However, the C-terminal domain of TLS was required for interaction with the serine-arginine (SR) splicing factor SC35 (SFRS2; 600813) and the TLS-associated SR proteins TASR1 and TASR2; this binding was lost in the TLS/ERG fusion protein because ERG replaced the C terminus of TLS. </p><p>Wang et al. (2008) showed that an RNA-binding protein, TLS, serves as a key transcriptional regulatory sensor of DNA damage signals that, on the basis of its allosteric modulation by RNA, specifically binds to and inhibits CREB-binding protein (CBP; 600140) and p300 histone acetyltransferase (602700) activities on a repressed gene target, cyclin D1 (CCND1; 168461), in human cell lines. Recruitment of TLS to the CCND1 promoter to cause gene-specific repression is directed by single-stranded, low copy-number noncoding RNA (ncRNA) transcripts tethered to the 5-prime regulatory regions of CCND1 that are induced in response to DNA damage signals. Wang et al. (2008) suggested that signal-induced noncoding RNAs localized to regulatory regions of transcription units can act cooperatively as selective ligands, recruiting and modulating the activities of distinct classes of RNA-binding coregulators in response to specific signals, providing an unexpected noncoding RNA/RNA-binding protein-based strategy to integrate transcriptional programs. </p><p>Using human prooncoprotein TLS purified from HeLa nuclear extracts, Baechtold et al. (1999) showed that TLS binds both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), with a 2-fold higher affinity for ssDNA. TLS can mediate the annealing of complementary ssDNAs, and this reaction requires Mg(2+), but not ATP. TLS was also found to promote the formation of stable D-loops in a homology-dependent manner during homologous recombination, again in the presence of Mg(2+), but not ATP. </p><p>Lerga et al. (2001) found that TLS specifically recognized RNA sequences containing a GGUG motif both in vitro and in vivo, and the specificity was determined by the cooperation between the RRM and RGG RNA binding domains of TLS. Analysis of TLS deletion mutants expressed in IW1-32 erythroid cells showed that these RNA binding domains of TLS are also responsible for the functional interference of TLS with in vivo splicing of pre-mRNAs. </p><p>Doi et al. (2008) found that TLS is one of the major nuclear polyQ aggregate-interacting proteins in a Huntington disease (HD; 143100) cell model, and binds directly to nuclear polyQ aggregates through its QSY-rich domain. Monitoring the kinetics of amyloid formation of expanded polyQ proteins in vitro and in vivo revealed that TLS inhibits polyQ aggregate growth. Further analysis demonstrated that TLS binding to polyQ amyloid and amorphous aggregates takes place at an early stage and interferes with amyloid formation before the formation of amyloid fibrils. Examination of polyQ aggregates in HD transgenic mouse brain revealed that TLS colocalizes with neuronal intranuclear inclusions (NIIs). Immunohistochemistry showed that TLS binds to neuronal intranuclear inclusions of human HD brain, suggesting that TLS participates in the pathogenesis of polyQ diseases. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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</span>
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</h4>
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<p>Ichikawa et al. (1994) and Panagopoulos et al. (1994) reported that the FUS gene was fused to the ERG gene in a patient with acute myeloid leukemia with a translocation t(16:21)(p11;q22). </p><p>Waters et al. (2000) described a 5.5-year-old girl who presented with a firm mass in her left forearm diagnosed as an angiomatoid fibrous histiocytoma (612160). Analysis of tumor tissue showed complex rearrangements between chromosomes 2, 12, 16, and 17 were noted on karyotypic study, as well as deletion in the long arm of chromosome 11. A t(12;16) site was investigated using RT-PCR. The FUS gene at 16p11.2 was found to be combined with the ATF1 gene (123803) at 12q13, generating a chimeric FUS/ATF1. Waters et al. (2000) found that FUS was interrupted at codon 175 and fused to codon 110 of ATF1, resulting in an in-frame junction with a glycine-to-valine (GGT-to-GTT) transition. </p><p>Low-grade fibromyxoid sarcoma (LGFMS) is a variant of fibrosarcoma. In 2 cases of soft tissue sarcoma that fulfilled morphologic criteria for LGFMS, Storlazzi et al. (2003) identified an FUS/CREB3L2 (608834) chimera, caused by a translocation between chromosome bands 7q33-q34 (CREB3L2) and 16p11 (FUS). A t(7;16)(q34;p11) translocation with the same or similar breakpoints had previously been reported in 5 other cases of LGFMS (Bejarano et al., 2000; Reid et al., 2003). To delineate the spectrum of tumors that may harbor the FUS/CREB3L2 fusion gene, Panagopoulos et al. (2004) selected 45 low-grade spindle cell sarcomas for study. None of these tumors had originally been diagnosed as LGFMS. Fourteen other tumors were also analyzed: 2 benign soft tissue tumors, 9 high-grade sarcomas with supernumerary ring chromosomes or 7q3 rearrangement, and 3 tumors diagnosed as LGFMS prior to genetic analysis. Of the 59 tumors studied, 12 were FUS/CREB3L2-positive, all of which were diagnosed at histopathologic reexamination as being LGFMS, of both the classic subtype and the subtype with giant collagen rosettes. The breakpoints in the fusion transcripts were always in exons 6 or 7 of FUS and exon 5 of CREB3L2. In the FUS/CREB3L2 chimera, the DNA binding and basic leucine zipper dimerization (bZIP)-encoding domain of CREB3L2 comes under the control of the FUS promoter, which, in turn, may cause deregulation of genes normally controlled by CREB3L2. </p>
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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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</h4>
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<p><strong><em>Amyotrophic Lateral Sclerosis 6</em></strong></p><p>
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Lattante et al. (2013) provided a review of FUS mutations associated with amyotrophic lateral sclerosis (ALS6; 608030). FUS mutations occur in about 5% of patients with familial ALS and in 1% of patients with sporadic disease. </p><p>In 17 different families with amyotrophic lateral sclerosis-6 (ALS6; 608030), Kwiatkowski et al. (2009) identified 13 different mutations in the FUS gene (see, e.g., 137070.0001-137070.0004), including 10 mutations in exon 15. Only 1 mutation (137070.0001) was found in homozygosity. Postmortem examination of 1 patient with the R521G mutation (137070.0002) showed loss of motor neurons in the anterior horn of the spinal cord and the hypoglossal nucleus. Immunostaining showed nuclear and cytoplasmic aggregation of FUS and diffuse ubiquitin positivity in nuclei in the patient tissue, but not control tissue, suggesting misfolding of a nuclear protein. In vitro RNA binding studies showed that the mutations did not affect binding of RNA oligomers. </p><p>Vance et al. (2009) identified 3 FUS mutations in 9 families with ALS6. All of the mutations had also been found by Kwiatkowski et al. (2009). Vance et al. (2009) demonstrated that wildtype endogenous FUS is predominantly localized to the nucleus. FUS mutations caused subcellular mislocalization with protein retention in the cytoplasm. Kwiatkowski et al. (2009) and Vance et al. (2009) estimated the frequency of FUS mutations to be about 5% in familial ALS. </p><p>Corrado et al. (2010) identified 7 different missense mutations, including 6 novel mutations, in the FUS gene (see, e.g., 137070.0006 and 137070.0007) in 9 of 1,009 Italian patients with ALS, including 964 patients with sporadic disease. Two of the 9 patients with an FUS mutation had a family history of the disorder. In addition, 8 different deletions and 2 insertions were identified in 2 glycine-rich regions in exons 5 and 6, but these were also found in controls and believed to represent triplet repeat length polymorphisms. Overall, pathogenic FUS mutations were found in 0.7% of sporadic and 4.4% of familial ALS in this population. </p><p>Hewitt et al. (2010) identified a heterozygous mutation in the FUS gene (137070.0008) in 2 (5%) of 42 patients with familial ALS. A different heterozygous mutation (137070.0006) was identified in 1 of 548 patients with sporadic ALS. Both mutations were located in the C-terminal region of the protein, which is important in regulating DNA and RNA binding. Hewitt et al. (2010) postulated that disruption of this region may disrupt subcellular distribution of FUS, in turn affecting transcription and RNA processing and conferring a toxic gain of function. </p><p>Millecamps et al. (2010) identified 5 different FUS mutations in 7 (4.3%) of 162 French probands with familial ALS. All mutations were located in exon 15 of the FUS gene. One patient with a FUS mutation (R521C; 137070.0004) was also heterozygous for a mutation in the ANG gene (K17I; 105850.0002), which causes ALS9 (611895). Overall, FUS mutation carriers had an earlier age of disease onset and shorter life span compared to those with mutations in other ALS genes. </p><p>Waibel et al. (2010) identified 2 different heterozygous mutations in the FUS gene (see, e.g., R495X; 137070.0009) in 4 (6.8%) of 58 German families with ALS. No FUS mutations were found in 133 patients with sporadic disease. The authors sequenced only the C-terminal region of the gene encompassing exons 13 to 15. </p><p>Yan et al. (2010) identified 16 heterozygous FUS mutations, including 11 novel mutations (see, e.g., G206S; 137070.0010), in 25 (5.6%) of 476 patients with familial ALS who did not have mutations in the SOD1 (147450) or TARDBP (605078) genes. All exons in the FUS gene were screened, but 12 of the 16 mutations were found in exons 14 and 15. No mutations were found in 41 patients with sporadic ALS. </p><p>Deng et al. (2010) studied postmortem spinal cord sections from 52 patients with sporadic ALS (SALS), 16 with familial ALS (FALS), 10 with ALS with dementia, and 11 with frontotemporal lobar degeneration (FTLD). Only 1 of the patients had an FUS mutation, and 4 had an SOD1 (147450) mutation. FUS-immunoreactivity was found in some of the surviving spinal motor neurons of all 52 patients with SALS, in 12 SOD1-negative FALS patients, and in 10 ALS with dementia patients. None of the 4 patients with SOD1 mutations had FUS-immunoreactive inclusions. The FUS-positive inclusions were skein-like and were found in the cytoplasm of large anterior horn neurons and their neurites. FUS-positive inclusions colocalized with ubiquitin (UBB; 191339) and p62 (601530), as well as with TDP43 (605078). Nine patients with FTLD had rare FUS-, UBB-, and TDP43-positive inclusions. Two patients with atypical FTLD also had FUS-positive inclusions, but these inclusions were negative for TDP43. The findings suggested that posttranslational modification of FUS is involved in a wider range of neurodegenerative disorders than FUS-related ALS, and also suggested that SOD1-related ALS has a distinct pathogenic pathway. </p><p>Ataxin-2 (ATXN2; 601517) is a polyglutamine protein that normally contains 22 repeats, but it contains 34 or more repeats in spinocerebellar ataxia-2 (SCA2; 183090). Intermediate repeat lengths (27 to 33) are associated with increased risk of ALS (see ALS13; 183090). Farg et al. (2013) found that ataxin-2 with 31 repeats (Q31) interacted with wildtype FUS and, more strongly, with FUS containing the R521C or arg521-to-his (R521H; 137070.0005) mutations. The interactions were independent of RNA. Western blot analysis revealed at least 3 low molecular mass FUS species (about 40 to 60 kD) in ALS patient tissues that did not coprecipitate with ataxin-2. Ataxin-2 colocalized with FUS in sporadic and FUS-linked familial ALS patient motor neurons, coprecipitated with FUS in ALS spinal cord lysates, and colocalized with FUS in the ER and Golgi compartments in a mouse neuronal cell line. Ataxin-2 Q31 exacerbated the cellular phenotype of mutant FUS, increasing translocation of FUS from the nucleus to the cytoplasm, markers of ER stress, and Golgi fragmentation. Neither FUS with the R521H mutation nor ataxin-2 Q31 alone induced apoptosis in transfected mouse neuronal cells, but coexpression of both induced markers of early apoptosis. </p><p>Vance et al. (2013) found that FUS proteins with ALS-linked mutations in the C-terminal nuclear localization signal accumulated in the cytoplasm of transfected cells and patient fibroblasts. Mutant, but not wildtype, FUS localized to cytoplasmic stress granules and interacted with the stress granule protein PABP (PABPC1; 604679) in an RNA-dependent manner. Addition of the wildtype C-terminal nuclear localization signal to full-length mutant FUS restored predominant nuclear localization. Sodium arsenite-induced oxidative stress caused formation of PABP-positive stress granules, with sequestration of mutant, but not wildtype, FUS to stress granules. Mutant FUS also interacted with wildtype FUS in an RNA-independent manner, and this interaction resulted in mislocalization of the wildtype protein to stress granules. Vance et al. (2013) hypothesized that FUS may function in shuttling nuclear RNA to cytoplasmic stress granules for degradation and that elevated cytoplasmic mutant FUS interferes with RNA processing. </p><p>Using a bioinformatics approach combined with in vitro cellular expression studies, Rebelo et al. (2016) identified FUS as a gene with the potential to cause abnormal and toxic protein aggregations as a result of a stop-loss mutation, i.e., a mutation that extends the 3-prime translation frame beyond the normal stop codon, resulting in the addition of cryptic amyloidogenic elements (CAE). Although this type of mutation had not yet been reported in FUS, neuronal cells expressing such frameshift FUS mutations showed prominent toxic protein aggregations in the cytoplasm and in neuronal projections, indicating that they would be pathogenic and thus could likely result in neurologic disorders. A similar gain-of-function mechanism was observed for frameshift mutations in the neurofilament genes NEFH (162230) and NEFL (162280). </p><p><strong><em>Hereditary Essential Tremor 4</em></strong></p><p>
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In affected members of a large family with hereditary essential tremor-4 (ETM4; 614782), Merner et al. (2012) identified a heterozygous mutation in the FUS gene (Q290X; 137070.0011) that segregated with the disorder in all patients who were determined to be 'definitely' or 'probably' affected. However, only 54% of those who were 'possibly' affected carried the mutation, and 1 unaffected individual who was 24 years old carried the mutation. The mutation was found by exome sequencing. The Q290X mutation was demonstrated to result in nonsense-mediated mRNA decay. Sequencing the FUS gene in 270 additional probands with essential tremor found that 3 patients had 2 different heterozygous mutations (R216C, 137070.0007 and P431L, 137070.0012). Two of these patients had a family history of the disorder, but family members were not available for study. ETM4 patient lymphoblastoid cells with the FUS mutations showed significantly lower overall expression of mutant FUS mRNA compared to cells from patients with ALS6 due to FUS mutations. In addition, ETM4 cells with the mutations showed a significant increase in FUS mRNA expression after treatment with the translation inhibitor puromycin, which was not seen with ALS6 FUS mutations. These findings indicated that truncating FUS mutations in ETM4 are associated with nonsense-mediated mRNA decay, whereas mutant FUS from ALS6 cells appear to escape nonsense-mediated mRNA decay. Thus, ETM4 may be due to loss of FUS function, whereas ALS6 may result from a toxic gain-of-function effect. </p>
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</span>
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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>The FUS protein contains an RNA-recognition motif and is a component of nuclear riboprotein complexes. FUS resembles a transcription factor in that it binds DNA, contributes a transcriptional activation domain to the FUS/ERG oncoprotein, and interacts with several transcription factors in vitro. By examining the consequences of Fus disruption in mice, Hicks et al. (2000) found that Fus was essential for viability of neonatal animals, influenced lymphocyte development in a non-cell-intrinsic manner, had an intrinsic role in the proliferative responses of B cells to specific mitogenic stimuli, and was required for the maintenance of genomic stability. The involvement of a nuclear riboprotein in these processes in vivo indicated that Fus is important in genome maintenance. </p><p>Shelkovnikova et al. (2013) generated transgenic mice expressing a truncated FUS protein (FUS1-359) that was predominantly cytoplasmic, highly aggregate-prone, and lacking a region responsible for RNA recognition and binding. Hemizygous mutant mice were indistinguishable from wildtype controls until age 2.5 to 4.5 months when they abruptly developed severe progressive motor dysfunction and died. Immunohistochemical analysis of the central nervous system of the mutant mice demonstrated that the truncated protein had rapidly aggregated and was able to seed aggregation of wildtype FUS protein. Additional analyses showed that the aggregation of FUS was sufficient to recapitulate the motor pathology of ALS in the mutant mice. </p><p>Shiihashi et al. (2016) created transgenic mice expressing neuronal-targeted human FUS that lacked its C-terminal nuclear localization signal (delta-NLS-FUS). Transgenic mice were born at the expected mendelian ratio and appeared normal in weight and behavior at birth. Delta-NLS-FUS was expressed exclusively in the cytoplasm in cortex and pyramidal tract of transgenic animals and accumulated in ubiquitin-positive inclusions. Expression of delta-NLS-FUS did not alter the amount or nuclear localization of endogenous mouse Fus. At 48 weeks, delta-NLS-FUS mice developed an abnormal hindlimb reflex and progressive motor weakness, prior to noticeable neuronal loss, which occurred at approximately 1 year. Cytoplasmic delta-NLS-FUS progressively reduced the number of nuclear Gemini of coiled bodies (GEMs) in cortical neurons, but not in spinal motor neurons. RNA sequence analysis revealed that delta-NLS-FUS altered expression of hundreds of genes, notably those regulating dynein-associated molecules and endoplasmic reticulum stress. Coexpression of human TDP43 (TARDBP; 605078) did not affect total neuronal content of TDP43 (exogenous plus endogenous), but exacerbated the phenotype of delta-NLS-FUS transgenic mice. </p><p>Lopez-Erauskin et al. (2018) generated FUS mice expressing full-length human FUS and found that when expressed at near endogenous mouse FUS levels, both wildtype and ALS-causing and frontotemporal dementia (FTD)-causing mutations (R521C and R521H) complemented the essential functions of mouse FUS. However, replacement of mouse FUS with only mutant human FUS resulted in stress-mediated induction of chaperones, decreased expression of ion channels and transporters essential for synaptic function, and reduced synaptic activity without loss of nuclear FUS or its cytoplasmic aggregation. The integrated stress response induced in mutant FUS impaired local protein synthesis within axons. ALS/FTD-linked FUS mutant mice developed progressive neurodegeneration, with age-dependent motor deficits and cognitive and memory deficits accompanied by astrogliosis, microgliosis, and loss of synapses in the hippocampus. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>12 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 6, AUTOSOMAL RECESSIVE</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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FUS, HIS517GLN
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<br />
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SNP: rs121909667,
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gnomAD: rs121909667,
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ClinVar: RCV000017608
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 4 affected members of a consanguineous family with amyotrophic lateral sclerosis-6 (ALS6; 608030), Kwiatkowski et al. (2009) identified a homozygous 1551C-G transversion in exon 15 of the FUS gene, resulting in a his517-to-gln (H517Q) substitution. The family originated from Cape Verde, a small island off the western coast of Africa. Three asymptomatic family members were also homozygous for the mutation, but all were younger than the mean age at disease onset of 45 years. The mutation was not detected in 1,446 control DNA samples from North America; 1 heterozygote was observed in 132 chromosomes from Cape Verde. </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 6 WITHOUT FRONTOTEMPORAL DEMENTIA</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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FUS, ARG521GLY
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<br />
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SNP: rs121909668,
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gnomAD: rs121909668,
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ClinVar: RCV000017609, RCV000703284, RCV002472932, RCV003421921
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with amyotrophic lateral sclerosis (ALS6; 608030) (Sapp et al., 2003), Kwiatkowski et al. (2009) identified a heterozygous 1561C-G transversion in exon 15 of the FUS gene, resulting in an arg521-to-gly (R521G) substitution. Inheritance was autosomal dominant with incomplete penetrance, and the mean age at onset was 39.6 years. Affected individuals from 2 additional unrelated ALS6 families also had the heterozygous R521G mutation. The mutation was not found in 1,446 control DNA samples. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA</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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FUS, ARG518LYS
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<br />
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SNP: rs121909669,
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ClinVar: RCV000017610, RCV005222688
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with amyotrophic lateral sclerosis (ALS6; 608030), Kwiatkowski et al. (2009) identified a heterozygous 1553G-A transition in exon 15 of the FUS gene, resulting in an arg518-to-lys (R518K) substitution. Inheritance was autosomal dominant, and the mean age at onset was 40.3 years. The mutation was not found in 1,446 control DNA samples. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 AMYOTROPHIC LATERAL SCLEROSIS 6 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA</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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FUS, ARG521CYS
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<br />
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SNP: rs121909668,
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gnomAD: rs121909668,
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ClinVar: RCV000017611, RCV001701569, RCV001851894, RCV004745160
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of 3 unrelated families with amyotrophic lateral sclerosis (ALS6; 608030), Kwiatkowski et al. (2009) identified a heterozygous 1561C-T transition in exon 15 of the FUS gene, resulting in an arg521-to-cys (R521C) in the C-terminal domain. The mutation was not found in 1,446 control DNA samples. </p><p>Vance et al. (2009) identified a heterozygous R521C mutation in 6 affected members of a British family with ALS6 (Ruddy et al., 2003) and in 3 affected members of an additional family with ALS and in 3 index ALS cases. </p><p>Corrado et al. (2010) identified a heterozygous R521C mutation in 2 unrelated Italian patients with ALS6. One had a family history of the disorder, and the other had sporadic disease. Onset occurred at age 34 and 54 years, respectively, and both had an unusual phenotype with proximal, mostly symmetric upper limb weakness with neck and axial involvement. </p><p>Millecamps et al. (2010) identified heterozygosity for the R521C mutation in 3 of 162 French probands with familial ALS. One patient was also heterozygous for a mutation in the ANG gene (K17I; 105850.0002), which causes ALS9 (611895), </p><p>Yan et al. (2010) identified heterozygosity for the R521C mutation in 6 families with ALS6: 4 were Caucasian, 1 was African American, and 1 was Chinese. Five families had classic ALS6. The proband in the remaining family had ALS, her brother had parkinsonism and dementia, and her mother and sister had dementia. These features expanded the phenotype associated with FUS mutations. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA</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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FUS, ARG521HIS
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<br />
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SNP: rs121909671,
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gnomAD: rs121909671,
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ClinVar: RCV000017612, RCV001851895, RCV003886363
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with autosomal dominant amyotrophic lateral sclerosis (ALS6; 608030), Kwiatkowski et al. (2009) identified a heterozygous 1562G-A transition in exon 15 of the FUS gene, resulting in an arg521-to-his (R521H) substitution. The mutation was not found in 1,446 control DNA samples. </p><p>Vance et al. (2009) identified a heterozygous R521H substitution in affected members of 2 families with ALS6 and 1 index case. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA</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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FUS, GLY507ASP
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<br />
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SNP: rs267606831,
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ClinVar: RCV000017613, RCV003764579, RCV004745161
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated Italian patients with sporadic amyotrophic lateral sclerosis (ALS6; 608030), Corrado et al. (2010) identified a heterozygous 1520G-A transition in exon 14 of the FUS gene, resulting in a gly507-to-asp (G507D) substitution in a conserved residue. The mutation was not found in 500 healthy controls. </p><p>Hewitt et al. (2010) identified a heterozygous G507D mutation in a U.K. man with predominantly lower motor neuron ALS involving both the lower and upper limbs. He had no family history of neurologic disease, had onset at age 69 years, and died of respiratory failure 42 months after symptom onset. Postmortem examination showed marked loss of lower motor neurons at all spinal levels and neuronal and glial cytoplasmic inclusions, which stained for FUS. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0007 AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA</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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TREMOR, HEREDITARY ESSENTIAL, 4, 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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FUS, ARG216CYS
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<br />
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SNP: rs267606832,
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gnomAD: rs267606832,
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ClinVar: RCV000017614, RCV000030719, RCV001588814, RCV002247351, RCV002513082, RCV004745162
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 1 of 1,009 Italian patients with amyotrophic lateral sclerosis (ALS6; 608030), Corrado et al. (2010) identified a heterozygous 646C-T transition in exon 6 of the FUS gene, resulting in an arg216-to-cys (R216C) substitution in a conserved residue. The mutation was not found in 793 controls. </p><p>In 2 of 270 unrelated patients with hereditary essential tremor-4 (ETM4; 614782), Merner et al. (2012) identified a heterozygous R216C substitution at a highly conserved residue in the glycine-rich domain. The mutation was found in 1 (0.1%) of 900 control alleles. One of the patients had a family history of the disorder, but family members were not available for study. The mutation disrupts a CpG site, which may cause an epigenetic effect on gene expression through changes in methylation. ETM4 patient lymphoblastoid cells showed significantly lower overall expression of mutant FUS mRNA than did cells from patients with ALS due to FUS mutations. In addition, ETM4 cells with the R216C mutation showed a significant increase in FUS mRNA expression after treatment with the translation inhibitor puromycin. </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>.0008 AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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FUS, ARG524TRP
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<br />
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SNP: rs267606833,
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ClinVar: RCV000017615, RCV001362689
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 3 U.K. patients, including 2 sibs, with amyotrophic lateral sclerosis (ALS6; 608030), Hewitt et al. (2010) identified a heterozygous 1570A-T transversion in exon 15 of the FUS gene, resulting in an arg524-to-trp (R524W) substitution. The mutation was not found in 293 controls. One of the patients had onset of a progressive muscular atrophy variant of motor neuron disease with upper limb onset at the age of 61 years. His brother presented with a similar pattern of disease at age 58, but DNA was not available. Postmortem examination of the first patient showed marked depletion of lower motor neurons with glial cytoplasmic and nuclear inclusions that stained for p62 (SQSTM1; 601530). There was FUS staining predominantly in the nucleus of neurons and glia, with some lower motor neurons showing strong cytoplasmic FUS expression. An affected brother and sister with the R524W mutation had classic limb-onset 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>
|
|
<span class="mim-font">
|
|
<strong>.0009 AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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FUS, ARG495TER
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<br />
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SNP: rs387906627,
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gnomAD: rs387906627,
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ClinVar: RCV000022556, RCV002247377, RCV003764624
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 3 affected members of a German family with amyotrophic lateral sclerosis (ALS6; 608030), Waibel et al. (2010) identified a heterozygous 1483C-T transition in exon 14 of the FUS gene, resulting in an arg495-to-ter (R495X) substitution predicted to produced a truncated protein lacking the nuclear localization sequence. The age at onset ranged from 31 to 36 years, with rapid disease progression leading to death 12 to 18 months later. All presented with bulbar signs and symptoms and had predominantly lower motor signs. None had dementia. </p><p>Yan et al. (2010) identified heterozygosity for the R495X mutation in a Caucasian family with ALS6. There was wide phenotypic variability: the age at onset ranged from 24 to 44 years in 4 mutation carriers, and 2 mutation carriers were unaffected at age 57 and 61 years, respectively. One mutation carrier had onset at age 14 years, and postmortem analysis was consistent with Fazio-Londe disease (211500). </p><p>Bosco et al. (2010) reported a 5-generation family with 8 affected members with early-onset ALS caused by the R495X mutation, which led to a relatively severe ALS clinical phenotype compared with FUS missense mutations. Expression of R495X FUS, which abrogates a putative nuclear localization signal at the C terminus of FUS, in HEK-293 cells and in the zebrafish spinal cord caused a striking cytoplasmic accumulation of the protein to a greater extent than that observed for recessive (H517Q; 137070.0001) and dominant (R521G; 137070.0002) missense mutants. In response to oxidative stress or heat-shock conditions in cultures and in vivo, the ALS-linked FUS mutants, but not wildtype FUS, assembled into perinuclear stress granules in proportion to their cytoplasmic expression levels. The authors proposed a potential link between FUS mutations and cellular pathways involved in stress responses that may be relevant to altered motor neuron homeostasis in ALS. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 AMYOTROPHIC LATERAL SCLEROSIS 6 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
FUS, GLY206SER
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<br />
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|
|
SNP: rs387906628,
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|
|
gnomAD: rs387906628,
|
|
|
|
|
|
ClinVar: RCV000022557
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family of South Korean origin with amyotrophic lateral sclerosis (ALS6; 608030), Yan et al. (2010) identified a heterozygous 616G-A transition in exon 6 of the FUS gene, resulting in a gly206-to-ser (G206S) substitution. The proband developed ALS at age 54 years, and his 2 brothers had behavior problems in their forties consistent with frontotemporal dementia. </p>
|
|
</span>
|
|
</div>
|
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 TREMOR, HEREDITARY ESSENTIAL, 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FUS, GLN290TER
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs387907274,
|
|
|
|
|
|
|
|
ClinVar: RCV000030720
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large family with hereditary essential tremor-4 (ETM4; 614782), Merner et al. (2012) identified a heterozygous 868C-T transition in exon 9 of the FUS gene, resulting in a gln290-to-ter (Q290X) substitution in the nuclear export signal motif. The mutation segregated with the disorder in all patients who were determined to be 'definitely' or 'probably' affected. However, only 54% of those who were 'possibly' affected carried the mutation, and 1 unaffected individual who was 24 years old also carried the mutation. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in 450 controls or in a large exome database. Studies of patient lymphoblastoid cells showed that the mutant mRNA was degraded by nonsense-mediated mRNA decay, resulting in haploinsufficiency. ETM4 patient lymphoblastoid cells showed significantly lower overall expression of mutant FUS mRNA than did cells from patients with ALS6 due to FUS mutations. None of the patients over the age of onset of amyotrophic lateral sclerosis had signs of that disorder. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 TREMOR, HEREDITARY ESSENTIAL, 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FUS, PRO431LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs186547381,
|
|
|
|
|
|
gnomAD: rs186547381,
|
|
|
|
|
|
ClinVar: RCV000030718, RCV000711709, RCV000765290, RCV001847624, RCV002381274, RCV003407373, RCV003993752
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with hereditary essential tremor-4 (ETM4; 614782), Merner et al. (2012) identified a heterozygous 1292C-T transition in exon 12 of the FUS gene, resulting in a pro431-to-leu (P431L) substitution at a highly conserved residue in the zinc finger domain. The patient had a family history of the disorder, but family members were not available for analysis. The mutation was not found in 450 controls. Although the mutation occurred in the last nucleotide of exon 12, no splicing abnormalities were detected. ETM4 patient lymphoblastoid cells showed significantly lower overall expression of mutant FUS mRNA than did cells from patients with ALS6 due to FUS mutations. In addition, ETM4 cells with the P431L mutation showed a significant increase in FUS mRNA expression after treatment with the translation inhibitor puromycin. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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|
|
|
<div>
|
|
<ol>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Aman, P., Panagopoulos, I., Lassen, C., Fioretos, T., Mencinger, M., Toresson, H., Hoglund, M., Forster, A., Rabbitts, T. H., Ron, D., Mandahl, N., Mitelman, F.
|
|
<strong>Expression patterns of the human sarcoma-associated genes FUS and EWS and the genomic structure of FUS.</strong>
|
|
Genomics 37: 1-8, 1996.
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|
|
[PubMed: 8921363]
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[Full Text: https://doi.org/10.1006/geno.1996.0513]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Baechtold, H., Kuroda, M., Sok, J., Ron, D., Lopez, B. S., Akhmedov, A. T.
|
|
<strong>Human 75-kDa DNA-pairing protein is identical to the pro-oncoprotein TLS/FUS and is able to promote D-loop formation.</strong>
|
|
J. Biol. Chem. 274: 34337-34342, 1999.
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[PubMed: 10567410]
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[Full Text: https://doi.org/10.1074/jbc.274.48.34337]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bejarano, P. A., Padhya, T. A., Smith, R., Blough, R., Devitt, J. J., Gluckman, J. L.
|
|
<strong>Hyalinizing spindle cell tumor with giant rosettes--a soft tissue tumor with mesenchymal and neuroendocrine features: an immunohistochemical, ultrastructural, and cytogenetic analysis.</strong>
|
|
Arch. Path. Lab. Med. 124: 1179-1184, 2000.
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[PubMed: 10923080]
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[Full Text: https://doi.org/10.5858/2000-124-1179-HSCTWG]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Bosco, D. A., Lemay, N., Ko, H. K., Zhou, H., Burke, C., Kwiatkowski, T. J., Jr., Sapp, P., McKenna-Yasek, D., Brown, R. H., Jr., Hayward, L. J.
|
|
<strong>Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules.</strong>
|
|
Hum. Molec. Genet. 19: 4160-4175, 2010.
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[PubMed: 20699327]
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[Full Text: https://doi.org/10.1093/hmg/ddq335]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Corrado, L., Del Bo, R., Castellotti, B., Ratti, A., Cereda, C., Penco, S., Soraru, G., Carlomagno, Y., Ghezzi, S., Pensato, V., Colombrita, C., Gagliardi, S., and 10 others.
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|
<strong>Mutations of FUS gene in sporadic amyotrophic lateral sclerosis.</strong>
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|
J. Med. Genet. 47: 190-194, 2010.
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[PubMed: 19861302]
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[Full Text: https://doi.org/10.1136/jmg.2009.071027]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Crozat, A., Aman, P., Mandahl, N., Ron, D.
|
|
<strong>Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma.</strong>
|
|
Nature 363: 640-644, 1993.
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[PubMed: 8510758]
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|
[Full Text: https://doi.org/10.1038/363640a0]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Deng, H.-X., Zhai, H., Bigio, E. H., Yan, J., Fecto, F., Ajroud, K., Mishra, M., Ajroud-Driss, S., Heller, S., Sufit, R., Siddique, N., Mugnaini, E., Siddique, T.
|
|
<strong>FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis.</strong>
|
|
Ann. Neurol. 67: 739-748, 2010.
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|
|
|
|
|
[PubMed: 20517935]
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|
|
[Full Text: https://doi.org/10.1002/ana.22051]
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</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Doi, H., Okamura, K., Bauer, P. O., Furukawa, Y., Shimizu, H., Kurosawa, M., Machida, Y., Miyazaki, H., Mitsui, K., Kuroiwa, Y., Nukina, N.
|
|
<strong>RNA-binding protein TLS is a major nuclear aggregate-interacting protein in huntingtin exon 1 with expanded polyglutamine-expressing cells.</strong>
|
|
J. Biol. Chem. 283: 6489-6500, 2008.
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|
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[PubMed: 18167354]
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|
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[Full Text: https://doi.org/10.1074/jbc.M705306200]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Eneroth, M., Mandahl, N., Heim, S., Willen, H., Rydholm, A., Alberts, K. A., Mitelman, F.
|
|
<strong>Localization of the chromosomal breakpoints of the t(12;16) in liposarcoma to subbands 12q13.3 and 16p11.2.</strong>
|
|
Cancer Genet. Cytogenet. 48: 101-107, 1990.
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|
|
[PubMed: 2372777]
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|
|
[Full Text: https://doi.org/10.1016/0165-4608(90)90222-v]
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Farg, M. A., Soo, K. Y., Warraich, S. T., Sundaramoorthy, V., Blair, I. P., Atkin, J. D.
|
|
<strong>Ataxin-2 interacts with FUS and intermediate-length polyglutamine expansions enhance FUS-related pathology in amyotrophic lateral sclerosis.</strong>
|
|
Hum. Molec. Genet. 22: 717-728, 2013. Note: Erratum: Hum. Molec. Genet. 29: 703-704, 2013.
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|
[PubMed: 23172909]
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[Full Text: https://doi.org/10.1093/hmg/dds479]
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Hewitt, C., Kirby, J., Highley, J. R., Hartley, J. A., Hibberd, R., Hollinger, H. C., Williams, T. L., Ince, P. G., McDermott, C. J., Shaw, P. J.
|
|
<strong>Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis.</strong>
|
|
Arch. Neurol. 67: 455-461, 2010.
|
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|
|
[PubMed: 20385912]
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[Full Text: https://doi.org/10.1001/archneurol.2010.52]
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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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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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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 : 02/11/2019<br>Bao Lige - updated : 01/31/2019<br>Patricia A. Hartz - updated : 09/06/2017<br>George E. Tiller - updated : 06/23/2017<br>Cassandra L. Kniffin - updated : 4/27/2016<br>Patricia A. Hartz - updated : 9/10/2013<br>Cassandra L. Kniffin - updated : 8/6/2013<br>Patricia A. Hartz - updated : 7/18/2013<br>Cassandra L. Kniffin - updated : 3/18/2013<br>Cassandra L. Kniffin - updated : 9/11/2012<br>Cassandra L. Kniffin - updated : 12/15/2010<br>Cassandra L. Kniffin - updated : 9/28/2010<br>Cassandra L. Kniffin - updated : 8/16/2010<br>Cassandra L. Kniffin - updated : 6/22/2010<br>Cassandra L. Kniffin - updated : 9/1/2009<br>Ada Hamosh - updated : 8/29/2008<br>Victor A. McKusick - updated : 8/13/2004<br>Victor A. McKusick - updated : 1/12/2001<br>Paul J. Converse - updated : 7/14/2000<br>Paul J. Converse - updated : 7/7/2000<br>Patti M. Sherman - updated : 6/20/2000<br>Victor A. McKusick - updated : 1/28/2000<br>Moyra Smith - updated : 12/13/1996
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Victor A. McKusick : 6/21/1993
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carol : 11/21/2024<br>carol : 11/09/2022<br>carol : 01/27/2021<br>carol : 01/26/2021<br>carol : 08/28/2020<br>carol : 02/12/2019<br>carol : 02/11/2019<br>alopez : 01/31/2019<br>alopez : 09/06/2017<br>carol : 07/31/2017<br>alopez : 06/23/2017<br>carol : 04/28/2016<br>ckniffin : 4/27/2016<br>carol : 7/8/2015<br>mgross : 9/10/2013<br>carol : 8/9/2013<br>ckniffin : 8/6/2013<br>mgross : 7/18/2013<br>carol : 7/17/2013<br>ckniffin : 3/18/2013<br>carol : 9/11/2012<br>ckniffin : 9/11/2012<br>carol : 11/22/2011<br>ckniffin : 3/17/2011<br>carol : 1/19/2011<br>carol : 1/19/2011<br>wwang : 1/7/2011<br>ckniffin : 12/15/2010<br>wwang : 9/29/2010<br>ckniffin : 9/28/2010<br>wwang : 8/19/2010<br>ckniffin : 8/16/2010<br>ckniffin : 8/16/2010<br>wwang : 6/28/2010<br>ckniffin : 6/22/2010<br>terry : 12/16/2009<br>alopez : 9/9/2009<br>wwang : 9/1/2009<br>ckniffin : 9/1/2009<br>carol : 10/9/2008<br>alopez : 9/11/2008<br>terry : 8/29/2008<br>carol : 8/5/2008<br>wwang : 7/9/2008<br>ckniffin : 7/3/2008<br>tkritzer : 8/13/2004<br>tkritzer : 8/13/2004<br>carol : 5/20/2003<br>cwells : 1/18/2001<br>terry : 1/12/2001<br>mgross : 7/14/2000<br>mgross : 7/7/2000<br>mcapotos : 6/23/2000<br>psherman : 6/20/2000<br>alopez : 1/31/2000<br>terry : 1/28/2000<br>joanna : 6/10/1997<br>jamie : 12/17/1996<br>mark : 12/13/1996<br>jenny : 12/12/1996<br>mark : 12/9/1996<br>carol : 3/28/1994<br>carol : 6/28/1993<br>carol : 6/21/1993
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