5507 lines
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5507 lines
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Entry
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- *605078 - TAR DNA-BINDING PROTEIN; TARDBP
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- OMIM
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<div class="container hidden-print">
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<div id="mimAlertBanner">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*605078</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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</li>
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<li role="presentation" 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/605078">Table View</a>
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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=ENSG00000120948;t=ENST00000240185" 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=23435" 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=605078" 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=ENSG00000120948;t=ENST00000240185" 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_007375,XR_007058558,XR_007058559,XR_007058560,XR_007058561,XR_007058562,XR_007058563,XR_007058564" 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_007375" 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=605078" 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=05466&isoform_id=05466_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/TARDBP" 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/901998,4886441,6678271,12044290,20140568,47939520,49065494,62897067,63100767,119592075,119592076,119592077,119592078,119592079,130750552,130750566,130750591,189065487,194381506,194388816,259465602,270123040,300639562,355469743,355469745,355469747,355469749,355469751" 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/Q13148" 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=23435" 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=ENSG00000120948;t=ENST00000240185" 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=TARDBP" 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=TARDBP" 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+23435" 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/TARDBP" 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:23435" 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/23435" 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=chr1&hgg_gene=ENST00000240185.8&hgg_start=11012654&hgg_end=11030528&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/gene-dosage/HGNC:11571" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:11571" 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/tardbp" 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=605078[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=605078[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/ENSG00000120948" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=TARDBP" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=TARDBP" 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=TARDBP" 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=TARDBP&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/PA36336" 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:11571" 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/FBgn0025790.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:2387629" 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/TARDBP#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:2387629" 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/23435/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://omia.org/OMIA002492/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=23435" 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=WBGene00006514;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-3777" 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:23435" 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=TARDBP&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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605078
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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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TAR DNA-BINDING PROTEIN; TARDBP
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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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
TAR DNA-BINDING PROTEIN, 43-KD; TDP43
|
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</span>
|
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</h4>
|
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</div>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TARDBP" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TARDBP</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/1/143?start=-3&limit=10&highlight=143">1p36.22</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:11012654-11030528&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'})">1:11,012,654-11,030,528</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
|
|
|
|
|
</span>
|
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</p>
|
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</div>
|
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|
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
</th>
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|
<th>
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|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/143?start=-3&limit=10&highlight=143">
|
|
1p36.22
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Amyotrophic lateral sclerosis 10, with or without FTD
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/612069"> 612069 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
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</tr>
|
|
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|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Frontotemporal lobar degeneration, TARDBP-related
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
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<span class="mim-font">
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<p>TARDBP is a predominantly nuclear RNA/DNA-binding protein that functions in RNA processing and metabolism, including RNA transcription, splicing, transport, and stability. Following cell stress, TARDBP also localizes to cytoplasmic stress granules and may play a role in stress granule formation (summary by <a href="#45" class="mim-tip-reference" title="Xia, Q., Wang, G., Wang, H., Hu, Q., Ying, Z. <strong>Folliculin, a tumor suppressor associated with Birt-Hogg-Dube (BHD) syndrome, is a novel modifier of TDP-43 cytoplasmic translocation and aggregation.</strong> Hum. Molec. Genet. 25: 83-96, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26516189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26516189</a>] [<a href="https://doi.org/10.1093/hmg/ddv450" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26516189">Xia et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26516189" 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>Human immunodeficiency virus (HIV)-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNA genome that produces a chromosomally integrated DNA during the replicative cycle. The HIV Tat protein (see <a href="/entry/601409">601409</a>), a transcription-activating protein that binds to the bulge region of a stable stem-bulge-loop structure, TAR RNA, activates the HIV-1 long terminal repeat (LTR). Tat activates the LTR less efficiently in rodent than in human cells, suggesting that cellular RNA-binding proteins are also involved in the regulation of HIV replication. TAR DNA may possess distinct regulatory elements that play a role in modulating HIV-1 gene expression. To characterize cellular factors that bind to TAR DNA, <a href="#31" class="mim-tip-reference" title="Ou, S.-H. I., Wu, F., Harrich, D., Garcia-Martinez, L. F., Gaynor, R. B. <strong>Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs.</strong> J. Virol. 69: 3584-3596, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7745706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7745706</a>] [<a href="https://doi.org/10.1128/JVI.69.6.3584-3596.1995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7745706">Ou et al. (1995)</a> screened a HeLa cell cDNA library using a TAR DNA probe and identified a cDNA encoding a 43-kD TAR DNA-binding protein, TARDBP, which they called TDP43. The deduced 414-amino acid TARDBP contains a ribonucleoprotein (RNP)-binding domain and a glycine-rich region. Northern blot analysis detected a ubiquitously expressed, 2.8-kb TARDBP transcript. SDS-PAGE analysis showed that recombinant and native TARDBP are expressed as 43-kD proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7745706" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By database analysis and cDNA cloning, <a href="#40" class="mim-tip-reference" title="Wang, H.-Y., Wang, I.-F., Bose, J., Shen, C.-K. J. <strong>Structural diversity and functional implications of the eukaryotic TDP gene family.</strong> Genomics 83: 130-139, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14667816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14667816</a>] [<a href="https://doi.org/10.1016/s0888-7543(03)00214-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14667816">Wang et al. (2004)</a> determined that the TARDBP gene generates at least 11 mRNA species by alternative splicing. The shorter transcripts encode proteins lacking the glycine-rich domain, which is required for the exon-skipping activity of TARDBP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14667816" 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="Benajiba, L., Le Ber, I., Camuzat, A., Lacoste, M., Thomas-Anterion, C., Couratier, P., Legallic, S., Salachas, F., Hannequin, D., Decousus, M., Lacomblez, L., Guedj, E., Golfier, V., Camu, W., Dubois, B., Campion, D., Meininger, V., Brice, A., French Clinical and Genetic Research Network on Frontotemporal Lobar Degeneration/Frontotemporal Lobar Degeneration with Motoneuron Disease. <strong>TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration.</strong> Ann. Neurol. 65: 470-474, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19350673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19350673</a>] [<a href="https://doi.org/10.1002/ana.21612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19350673">Benajiba et al. (2009)</a> stated that TDP43 contains 2 RNA recognition motifs, a nuclear export domain, and a C-terminal domain that is essential for binding to heterogeneous nuclear ribonucleoproteins (hnRNPs) and for splicing inhibition. TDP43 is normally localized in the nucleus, but in pathologic conditions, the cleaved form of TDP43 is mainly present in the cytoplasm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19350673" 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="#40" class="mim-tip-reference" title="Wang, H.-Y., Wang, I.-F., Bose, J., Shen, C.-K. J. <strong>Structural diversity and functional implications of the eukaryotic TDP gene family.</strong> Genomics 83: 130-139, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14667816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14667816</a>] [<a href="https://doi.org/10.1016/s0888-7543(03)00214-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14667816">Wang et al. (2004)</a> determined that the TARDBP gene contains 6 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14667816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By genomic sequence analysis, <a href="#40" class="mim-tip-reference" title="Wang, H.-Y., Wang, I.-F., Bose, J., Shen, C.-K. J. <strong>Structural diversity and functional implications of the eukaryotic TDP gene family.</strong> Genomics 83: 130-139, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14667816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14667816</a>] [<a href="https://doi.org/10.1016/s0888-7543(03)00214-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14667816">Wang et al. (2004)</a> mapped the TARDBP gene to chromosome 1p36.21. They also identified intronless TARDBP-like pseudogenes on chromosomes 2, 6, 8, 13, and 20 that likely originated from retrotransposition events. <a href="#40" class="mim-tip-reference" title="Wang, H.-Y., Wang, I.-F., Bose, J., Shen, C.-K. J. <strong>Structural diversity and functional implications of the eukaryotic TDP gene family.</strong> Genomics 83: 130-139, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14667816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14667816</a>] [<a href="https://doi.org/10.1016/s0888-7543(03)00214-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14667816">Wang et al. (2004)</a> mapped the mouse Tardbp gene to chromosome 4E2 in a region that shows homology of synteny to human chromosome 1p36. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14667816" 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>Functional analysis by <a href="#31" class="mim-tip-reference" title="Ou, S.-H. I., Wu, F., Harrich, D., Garcia-Martinez, L. F., Gaynor, R. B. <strong>Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs.</strong> J. Virol. 69: 3584-3596, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7745706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7745706</a>] [<a href="https://doi.org/10.1128/JVI.69.6.3584-3596.1995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7745706">Ou et al. (1995)</a> indicated that TARDBP does not bind RNA. Gel retardation analysis followed by Western blot analysis (Shift-Western analysis) demonstrated that the RNP-binding motifs of TARDBP bind to the pyrimidine-rich motifs of TAR DNA. In an in vitro transcription analysis, increasing amounts of TARDBP, in the presence or absence of Tat, decreased the level of transcription from the HIV-1 LTR but not from the adenovirus major late promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7745706" 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 reporter plasmids, <a href="#40" class="mim-tip-reference" title="Wang, H.-Y., Wang, I.-F., Bose, J., Shen, C.-K. J. <strong>Structural diversity and functional implications of the eukaryotic TDP gene family.</strong> Genomics 83: 130-139, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14667816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14667816</a>] [<a href="https://doi.org/10.1016/s0888-7543(03)00214-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14667816">Wang et al. (2004)</a> determined that deletion of the glycine-rich domain of mouse Tardbp resulted in loss of about 90% of its ability to activate exon skipping in the CFTR gene (<a href="/entry/602421">602421</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14667816" 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>RNA splicing mutations in the CFTR gene are thought to lead to dysfunction of several organs such as lung, sweat glands, genital tract, intestine and pancreas, producing the complex symptoms of cystic fibrosis (<a href="/entry/219700">219700</a>). <a href="#8" class="mim-tip-reference" title="Buratti, E., Dork, T., Zucatto, E., Pagani, R., Romano, M., Baralle, F. E. <strong>Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping.</strong> EMBO J. 20: 1774-1784, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11285240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11285240</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11285240[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/emboj/20.7.1774" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11285240">Buratti et al. (2001)</a> showed that TDP43 promotes skipping of exon 9 of the CFTR gene by binding specifically to the UG repeat sequence in intron 8 of the CFTR pre-mRNA. <a href="#6" class="mim-tip-reference" title="Buratti, E., Baralle, F. E. <strong>Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9.</strong> J. Biol. Chem. 276: 36337-36343, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11470789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11470789</a>] [<a href="https://doi.org/10.1074/jbc.M104236200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11470789">Buratti and Baralle (2001)</a> reported the characterization and functional implications of the RNA binding properties of TDP43. <a href="#40" class="mim-tip-reference" title="Wang, H.-Y., Wang, I.-F., Bose, J., Shen, C.-K. J. <strong>Structural diversity and functional implications of the eukaryotic TDP gene family.</strong> Genomics 83: 130-139, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14667816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14667816</a>] [<a href="https://doi.org/10.1016/s0888-7543(03)00214-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14667816">Wang et al. (2004)</a> found that the mouse homolog of human TDP43 also inhibits human CFTR exon 9 splicing in a minigene system. <a href="#7" class="mim-tip-reference" title="Buratti, E., Brindisi, A., Pagani, F., Baralle, F. E. <strong>Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: a functional link with disease penetrance. (Letter)</strong> Am. J. Hum. Genet. 74: 1322-1325, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15195661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15195661</a>] [<a href="https://doi.org/10.1086/420978" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15195661">Buratti et al. (2004)</a> described experiments consistent with the model in which the TG repeats in the CFTR intron 8 bind to TDP43, and this protein, in turn, inhibits splicing of exon 9. They suggested that their results provide a mechanistic explanation for the association data of <a href="#17" class="mim-tip-reference" title="Groman, J. D., Hefferon, T. W., Casals, T., Bassas, L., Estivill, X., Georges, M. D., Guittard, C., Koudova, M., Fallin, M. D., Nemeth, K., Fekete, G., Kadasi, L., and 15 others. <strong>Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign.</strong> Am. J. Hum. Genet. 74: 176-179, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14685937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14685937</a>] [<a href="https://doi.org/10.1086/381001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14685937">Groman et al. (2004)</a> and also an explanation for the variable phenotypic penetrance of the TG repeats. Individual and tissue-specific variability in the concentration of this inhibitory splicing factor may even determine whether an individual will develop multisystemic (non-classic CF) or monosymptomatic (CBAVD) disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14685937+11470789+14667816+15195661+11285240" 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="Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., McCluskey, L. F., Miller, B. L., Masliah, E., Mackenzie, I. R., Feldman, H., Feiden, W., Kretzschmar, H. A., Trojanowski, J. Q., Lee, V. M.-Y. <strong>Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.</strong> Science 314: 130-133, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17023659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17023659</a>] [<a href="https://doi.org/10.1126/science.1134108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17023659">Neumann et al. (2006)</a> found that a hyperphosphorylated, ubiquitinated, and cleaved form of TDP43, known as pathologic TDP43, is the major disease protein in ubiquitin-positive, tau-, and alpha-synuclein-negative frontotemporal dementia (FTLD-U; <a href="/entry/607485">607485</a>) and in ALS (see <a href="/entry/105400">105400</a>). The signature of pathologic TDP43 in FTLD-U includes the presence of C-terminal breakdown and/or cleavage products migrating at approximately 25 kD, a 45 kD variant, and a high molecular weight TDP43-immunoreactive smear. TDP43 is normally localized primarily to the nucleus, but <a href="#30" class="mim-tip-reference" title="Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., McCluskey, L. F., Miller, B. L., Masliah, E., Mackenzie, I. R., Feldman, H., Feiden, W., Kretzschmar, H. A., Trojanowski, J. Q., Lee, V. M.-Y. <strong>Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.</strong> Science 314: 130-133, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17023659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17023659</a>] [<a href="https://doi.org/10.1126/science.1134108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17023659">Neumann et al. (2006)</a> suggested that, under pathologic conditions in FTLD-U, TDP43 is eliminated from nuclei of ubiquitinated inclusion-bearing neurons, a consequence of which may be a loss of TDP43 nuclear functions. <a href="#1" class="mim-tip-reference" title="Arai, T., Hasegawa, M., Akiyama, H., Ikeda, K., Nonaka, T., Mori, H., Mann, D., Tsuchiya, K., Yoshida, M., Hashizume, Y., Oda, T. <strong>TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.</strong> Biochem. Biophys. Res. Commun. 351: 602-611, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17084815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17084815</a>] [<a href="https://doi.org/10.1016/j.bbrc.2006.10.093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17084815">Arai et al. (2006)</a> also identified TDP43 as a component of ubiquitin-positive tau-negative neuronal and glial inclusions in frontotemporal lobar degeneration and ALS. Biochemical analysis suggested that abnormal phosphorylation of TDP43 may be involved in the pathogenesis of these disorders. The findings were similar to those reported by <a href="#30" class="mim-tip-reference" title="Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., McCluskey, L. F., Miller, B. L., Masliah, E., Mackenzie, I. R., Feldman, H., Feiden, W., Kretzschmar, H. A., Trojanowski, J. Q., Lee, V. M.-Y. <strong>Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.</strong> Science 314: 130-133, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17023659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17023659</a>] [<a href="https://doi.org/10.1126/science.1134108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17023659">Neumann et al. (2006)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17084815+17023659" 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="#27" class="mim-tip-reference" title="Mackenzie, I. R. A., Bigio, E. H., Ince, P. G., Geser, F., Neumann, M., Cairns, N. J., Kwong, L. K., Forman, M. S., Ravits, J., Stewart, H., Eisen, A., McClusky, L., Kretzschmar, H. A., Monoranu, C. M., Highley, J. R., Kirby, J., Siddique, T., Shaw, P. J., Lee, V. M.-Y., Trojanowski, J. Q. <strong>Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations.</strong> Ann. Neurol. 61: 427-434, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17469116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17469116</a>] [<a href="https://doi.org/10.1002/ana.21147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17469116">Mackenzie et al. (2007)</a> identified TDP43-immunoreactive neuronal and glial cytoplasmic inclusions in 59 cases of sporadic ALS, 26 cases of ALS with dementia, and 11 cases of SOD1 (<a href="/entry/147450">147450</a>)-negative familial ALS. Immunofluorescence confirmed colocalization of TDP43 and ubiquitin within the inclusions. In contrast, TDP43 was not detected in any of 15 patients with SOD1-positive ALS. The authors suggested that these findings represented differing pathogenic mechanisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17469116" 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="#14" class="mim-tip-reference" title="Elden, A. C., Kim, H.-J., Hart, M. P., Chen-Plotkin, A. S., Johnson, B. S., Fang, X., Armakola, M., Geser, F., Greene, R., Lu, M. M., Padmanabhan, A., Clay-Falcone, D., and 11 others. <strong>Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.</strong> Nature 466: 1069-1075, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20740007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20740007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20740007[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/nature09320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20740007">Elden et al. (2010)</a> showed that ataxin-2 (<a href="/entry/601517">601517</a>), a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2 (<a href="/entry/183090">183090</a>), is a potent modifier of TDP43 toxicity in animal and cellular models of ALS. ATXN2 and TDP43 associate in a complex that depends on RNA. In spinal cord neurons of ALS patients, ATXN2 is abnormally localized; likewise, TDP43 shows mislocalization in spinocerebellar ataxia-2. To assess the involvement of ATXN2 in ALS, <a href="#14" class="mim-tip-reference" title="Elden, A. C., Kim, H.-J., Hart, M. P., Chen-Plotkin, A. S., Johnson, B. S., Fang, X., Armakola, M., Geser, F., Greene, R., Lu, M. M., Padmanabhan, A., Clay-Falcone, D., and 11 others. <strong>Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.</strong> Nature 466: 1069-1075, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20740007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20740007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20740007[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/nature09320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20740007">Elden et al. (2010)</a> analyzed the length of the polyQ repeat in the ATXN2 gene in 915 ALS patients and 980 controls. The authors found that intermediate-length polyQ expansions (27 to 33 glutamines) in ATXN2 were significantly associated with ALS (4.7% of cases; 1.4% of controls). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20740007" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Armakola, M., Higgins, M. J., Figley, M. D., Barmada, S. J., Scarborough, E. A., Diaz, Z., Fang, X., Shorter, J., Krogan, N. J., Finkbeiner, S., Farese, R. V., Jr., Gitler, A. D. <strong>Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models.</strong> Nature Genet. 44: 1302-1309, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23104007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23104007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23104007[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/ng.2434" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23104007">Armakola et al. (2012)</a> reported results from 2 genomewide loss-of-function TDP43 toxicity suppressor screens in yeast. The strongest suppressor of TDP43 toxicity was deletion of DBR1 (<a href="/entry/607024">607024</a>), which encodes an RNA lariat debranching enzyme. <a href="#2" class="mim-tip-reference" title="Armakola, M., Higgins, M. J., Figley, M. D., Barmada, S. J., Scarborough, E. A., Diaz, Z., Fang, X., Shorter, J., Krogan, N. J., Finkbeiner, S., Farese, R. V., Jr., Gitler, A. D. <strong>Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models.</strong> Nature Genet. 44: 1302-1309, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23104007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23104007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23104007[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/ng.2434" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23104007">Armakola et al. (2012)</a> showed that, in the absence of DBR1 enzymatic activity, intronic lariats accumulate in the cytoplasm and likely act as decoys to sequester TDP43, preventing it from interfering with essential cellular RNAs and RNA-binding proteins. Knockdown of DBR1 in a human neuronal cell line or in primary rat neurons was also sufficient to rescue TDP43 toxicity. <a href="#2" class="mim-tip-reference" title="Armakola, M., Higgins, M. J., Figley, M. D., Barmada, S. J., Scarborough, E. A., Diaz, Z., Fang, X., Shorter, J., Krogan, N. J., Finkbeiner, S., Farese, R. V., Jr., Gitler, A. D. <strong>Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models.</strong> Nature Genet. 44: 1302-1309, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23104007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23104007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23104007[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/ng.2434" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23104007">Armakola et al. (2012)</a> concluded that their findings provided insight into TDP43-mediated cytotoxicity and suggested that decreasing DBR1 activity could be a potential therapeutic approach for ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23104007" 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="#25" class="mim-tip-reference" title="Ling, J. P., Pletnikova, O., Troncoso, J. C., Wong, P. C. <strong>TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD.</strong> Science 349: 650-655, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26250685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26250685</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26250685[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.aab0983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26250685">Ling et al. (2015)</a> found that depletion of Tardbp in mouse embryonic stem cells resulted in the splicing of cryptic exons into mRNA, often disrupting their translation and promoting nonsense-mediated mRNA decay. Similar results were observed in human HeLa cells. Enforced repression of cryptic exons prevented cell death in Tardbp-deficient cells. The findings suggested that TARDBP normally acts to repress the splicing of nonconserved cryptic exons, thereby maintaining intron integrity. Postmortem brain tissue from patients with ALS/FTD showed that repression of cryptic exons was impaired, suggesting that this splicing defect could contribute to TARDBP-proteinopathy in certain neurodegenerative diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26250685" 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 immunoprecipitation analysis of transfected HEK293 cells, followed by protein pull-down assays, <a href="#45" class="mim-tip-reference" title="Xia, Q., Wang, G., Wang, H., Hu, Q., Ying, Z. <strong>Folliculin, a tumor suppressor associated with Birt-Hogg-Dube (BHD) syndrome, is a novel modifier of TDP-43 cytoplasmic translocation and aggregation.</strong> Hum. Molec. Genet. 25: 83-96, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26516189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26516189</a>] [<a href="https://doi.org/10.1093/hmg/ddv450" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26516189">Xia et al. (2016)</a> showed that folliculin (FLCN; <a href="/entry/607273">607273</a>) interacted directly with TDP43. Overexpression of FLCN led to localization of TDP43 in cytoplasm, where it colocalized with markers of lysosomes, autophagosomes, and the ubiquitin-proteasome system. Under arsenite stress, TDP43 colocalized with stress granules. In contrast, RNA interference-mediated depletion of FLCN in arsenite-treated cells caused dissociation of TDP43 from stress granules and nuclear accumulation of TDP43. <a href="#45" class="mim-tip-reference" title="Xia, Q., Wang, G., Wang, H., Hu, Q., Ying, Z. <strong>Folliculin, a tumor suppressor associated with Birt-Hogg-Dube (BHD) syndrome, is a novel modifier of TDP-43 cytoplasmic translocation and aggregation.</strong> Hum. Molec. Genet. 25: 83-96, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26516189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26516189</a>] [<a href="https://doi.org/10.1093/hmg/ddv450" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26516189">Xia et al. (2016)</a> concluded that FLCN is critical for TDP43 translocation from nucleus to cytoplasm, which is required for stress granule assembly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26516189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#44" class="mim-tip-reference" title="Woerner, A. C., Frottin, F., Hornburg, D., Feng, L. R., Meissner, F., Patra, M., Tatzelt, J., Mann, M., Winklhofer, K. F., Hartl, F. U., Hipp, M. S. <strong>Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA.</strong> Science 351: 173-176, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26634439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26634439</a>] [<a href="https://doi.org/10.1126/science.aad2033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26634439">Woerner et al. (2016)</a> analyzed the compartment specificity of aggregate toxicity using artificial beta-sheet proteins, as well as fragments of mutant huntingtin (<a href="/entry/613004">613004</a>) and TDP43. Aggregation in the cytoplasm interfered with nucleocytoplasmic protein and RNA transport. In contrast, the same proteins did not inhibit transport when forming inclusions in the nucleus at or around the nucleolus. Protein aggregation in the cytoplasm, but not the nucleus, caused the sequestration and mislocalization of proteins containing disordered and low-complexity sequences, including multiple factors of the nuclear import and export machinery. Thus, <a href="#44" class="mim-tip-reference" title="Woerner, A. C., Frottin, F., Hornburg, D., Feng, L. R., Meissner, F., Patra, M., Tatzelt, J., Mann, M., Winklhofer, K. F., Hartl, F. U., Hipp, M. S. <strong>Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA.</strong> Science 351: 173-176, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26634439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26634439</a>] [<a href="https://doi.org/10.1126/science.aad2033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26634439">Woerner et al. (2016)</a> concluded that impairment of nucleocytoplasmic transport may contribute to the cellular pathology of various aggregate deposition diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26634439" 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 decrease in ataxin-2 (<a href="/entry/601517">601517</a>) suppresses TDP43 toxicity in yeast and flies, and intermediate-length polyglutamine expansions in the ataxin-2 gene increase the risk of ALS (see <a href="/entry/183090">183090</a>). <a href="#4" class="mim-tip-reference" title="Becker, L. A., Huang, B., Bieri, G., Ma, R., Knowles, D. A., Jafar-Nejad, P., Messing, J., Kim, H. J., Soriano, A., Auburger, G., Pulst, S. M., Taylor, J. P., Rigo, F., Gitler, A. D. <strong>Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice.</strong> Nature 544: 367-371, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28405022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28405022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28405022[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/nature22038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28405022">Becker et al. (2017)</a> used 2 independent approaches to test whether decreasing ataxin-2 levels could mitigate disease in a mouse model of TDP43 proteinopathy. First, they crossed ataxin-2 knockout mice with TDP43 transgenic mice. The decrease in ataxin-2 reduced aggregation of TDP43, markedly increased survival, and improved motor function. Second, in a more therapeutically applicable approach, <a href="#4" class="mim-tip-reference" title="Becker, L. A., Huang, B., Bieri, G., Ma, R., Knowles, D. A., Jafar-Nejad, P., Messing, J., Kim, H. J., Soriano, A., Auburger, G., Pulst, S. M., Taylor, J. P., Rigo, F., Gitler, A. D. <strong>Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice.</strong> Nature 544: 367-371, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28405022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28405022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28405022[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/nature22038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28405022">Becker et al. (2017)</a> administered antisense oligonucleotides targeting ataxin-2 to the central nervous system of TDP43 transgenic mice. This single treatment markedly extended survival. <a href="#4" class="mim-tip-reference" title="Becker, L. A., Huang, B., Bieri, G., Ma, R., Knowles, D. A., Jafar-Nejad, P., Messing, J., Kim, H. J., Soriano, A., Auburger, G., Pulst, S. M., Taylor, J. P., Rigo, F., Gitler, A. D. <strong>Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice.</strong> Nature 544: 367-371, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28405022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28405022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28405022[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/nature22038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28405022">Becker et al. (2017)</a> suggested that because TDP43 aggregation is a component of nearly all cases of ALS, targeting ataxin-2 could represent a broadly effective therapeutic strategy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28405022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#39" class="mim-tip-reference" title="Vogler, T. O., Wheeler, J. R., Nguyen, E. D., Hughes, M. P., Britson, K. A., Lester, E., Rao, B., Dalla Betta, N., Whitney, O. N., Ewachiw, T. E., Gomes, E., Shorter, J., Lloyd, T. E., Eisenberg, D. S., Taylor, J. P., Johnson, A. M., Olwin, B. B., Parker, R. <strong>TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle.</strong> Nature 563: 508-513, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30464263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30464263</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30464263[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/s41586-018-0665-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30464263">Vogler et al. (2018)</a> demonstrated that TDP43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which the authors termed myogranules, during regeneration of skeletal muscle in mice and humans. Myogranules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibers mature. Although myogranules occur during normal skeletal muscle regeneration, myogranules can seed TDP43 amyloid fibrils in vitro and were increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myogranules could be the source of cytoplasmic TDP43 aggregates that commonly occur in neuromuscular diseases such as ALS and inclusion body myopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30464263" 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="Taylor, L. M., McMillan, P. J., Liachko, N. F., Strovas, T. J., Ghetti, B., Bird, T. D., Keene, C. D., Kraemer, B. C. <strong>Pathological phosphorylation of tau and TDP-43 by TTBK1 and TTBK2 drives neurodegeneration.</strong> Molec. Neurodegener. 13: 7, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29409526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29409526</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29409526[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/10.1186/s13024-018-0237-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29409526">Taylor et al. (2018)</a> showed that patients with FTLD with tau inclusions (see <a href="/entry/600274">600274</a>) or TDP43 inclusions had elevated expression of both TTBK1 (<a href="/entry/619415">619415</a>) and TTBK2 (<a href="/entry/611695">611695</a>) in cortical and hippocampal neurons and that TTBK1 and TTBK2 colocalized with phosphorylated proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29409526" 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="#32" class="mim-tip-reference" title="Shao, W., Todd, T. W., Wu, Y., Jones, C. Y., Tong, J., Jansen-West, K., Daughrity, L. M., Park, J., Koike, Y., Kurti, A., Yue, M., Castanedes-Casey, M., and 11 others. <strong>Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration.</strong> Science 378: 94-99, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36201573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36201573</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36201573[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.abq7860" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36201573">Shao et al. (2022)</a> studied the interplay of the FTD-ALS-associated genes C9ORF72 (<a href="/entry/614260">614260</a>), TBK1 (<a href="/entry/604834">604834</a>), and TDP43. <a href="#32" class="mim-tip-reference" title="Shao, W., Todd, T. W., Wu, Y., Jones, C. Y., Tong, J., Jansen-West, K., Daughrity, L. M., Park, J., Koike, Y., Kurti, A., Yue, M., Castanedes-Casey, M., and 11 others. <strong>Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration.</strong> Science 378: 94-99, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36201573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36201573</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36201573[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.abq7860" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36201573">Shao et al. (2022)</a> found that TBK1 is phosphorylated in response to C9ORF72 poly(gly-ala; GA) aggregation and sequestered into inclusions, resulting in decreased TBK1 activity and contributing to neurodegeneration. Reducing TBK1 activity in mice using a knockin mutation exacerbated poly(GA)-induced phenotypes, including increased TDP43 pathology and the accumulation of defective endosomes in poly(GA)-positive neurons. The authors postulated a disruption of the endosomal-lysosomal pathway in FTD-ALS, leading to increased susceptibility to protein aggregation, driving TDP43 proteinopathy and neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36201573" 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="#18" class="mim-tip-reference" title="Hruska-Plochan, M., Wiersma, V. I., Betz, K. M., Mallona, I., Ronchi, S., Maniecka, Z., Hock, E. M., Tantardini, E., Laferriere, F., Sahadevan, S., Hoop, V., Delvendahl, I., and 15 others. <strong>A model of human neural networks reveals NPTX2 pathology in ALS and FTLD.</strong> Nature 626: 1073-1083, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38355792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38355792</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38355792[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/s41586-024-07042-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38355792">Hruska-Plochan et al. (2024)</a> generated human neural stem cells from induced pluripotent stem cells derived from normal human skin fibroblasts and found that they were self-renewing and could form functional networks, which the authors called iNets, with neuronal and glial maturation similar to that of cortical organoids. Overexpression of wildtype TDP43 in a minority of neurons within iNets led to progressive fragmentation and aggregation of TDP43, resulting in partial loss of function and neurotoxicity. Single-cell transcriptomic analysis revealed a novel set of misregulated RNA targets in TDP43-overexpressing neurons and in patients with TDP43 proteinopathies exhibiting loss of nuclear TDP43. The strongest misregulated target was NPTX2 (<a href="/entry/600750">600750</a>), whose levels were controlled by TDP43 binding to its 3-prime UTR. NPTX2 exhibited neurotoxicity when overexpressed in iNets, whereas correcting NPTX2 misregulation partially rescued neurons from TDP43-induced neurodegeneration. NPTX2 was consistently misaccumulated in neurons from patients with ALS and frontotemporal lobar degeneration with TDP43 pathology. The results directly linked TDP43 misregulation and NPTX2 accumulation, thereby revealing a TDP43-dependent pathway of neurotoxicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38355792" 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="#24" 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 TARDBP mutations associated with ALS10 (<a href="/entry/612069">612069</a>). TARDPB mutations occur in about 3% of patients with familial ALS and in 1.5% 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><a href="#16" class="mim-tip-reference" title="Gitcho, M. A., Bigio, E. H., Mishra, M., Johnson, N., Weintraub, S., Mesulam, M., Rademakers, R., Chakraverty, S., Cruchaga, C., Morris, J. C., Goate, A. M., Cairns, N. J. <strong>TARDBP 3-prime-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy.</strong> Acta Neuropath. 118: 633-645, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19618195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19618195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19618195[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/10.1007/s00401-009-0571-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19618195">Gitcho et al. (2009)</a> noted that TDP43 was first identified as the major pathologic protein of ubiquitin-positive, tau-negative inclusions of frontotemporal lobar degeneration (FTLDU; <a href="/entry/607485">607485</a>), FTLD with motor neuron disease (FTDMND; <a href="/entry/105500">105500</a>), and ALS/MND (ALS10). These disorders are now considered to represent different clinical manifestations of the same underlying molecular pathology, namely TDP43 proteinopathy. The differing clinical phenotypes of these overlapping disorders most likely reflect the selective vulnerability of different segments of the neuraxis to neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19618195" 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 a family segregating autosomal dominant ALS and 2 sporadic cases (see ALS10, <a href="/entry/612069">612069</a>), <a href="#33" class="mim-tip-reference" title="Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J. C., Williams, K. L., Buratti, E., Baralle, F., de Belleroche, J., Mitchell, J. D., Leigh, P. N., Al-Chalabi, A., Miller, C. C., Nicholson, G., Shaw, C. E. <strong>TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis.</strong> Science 319: 1668-1672, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18309045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18309045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18309045[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.1154584" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18309045">Sreedharan et al. (2008)</a> identified mutations in the TARDBP gene. All 3 mutations, M337V (<a href="#0001">605078.0001</a>), Q331K (<a href="#0002">605078.0002</a>), and G294A (<a href="#0001">605078.0001</a>) occurred in a highly conserved region of the C terminus of TDP43 involved in protein-protein interactions. To assess the functional significance of these mutations, <a href="#33" class="mim-tip-reference" title="Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J. C., Williams, K. L., Buratti, E., Baralle, F., de Belleroche, J., Mitchell, J. D., Leigh, P. N., Al-Chalabi, A., Miller, C. C., Nicholson, G., Shaw, C. E. <strong>TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis.</strong> Science 319: 1668-1672, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18309045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18309045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18309045[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.1154584" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18309045">Sreedharan et al. (2008)</a> expressed tagged TDP43(wildtype), TDP43(Q331K), and TDP43(M337V) in Chinese hamster ovary (CHO) cells. Immunofluorescent staining of cells 48 hours after transfection showed abundant expression of transfected TDP43, with no obvious differences in subcellular distribution or aggregation between mutant and wildtype proteins. Expression of these tagged proteins in spinal cord of stage 14 chick embryos demonstrated dramatic reduction in maturation in embryos expressing mutant versus wildtype TDP43, with a failure to develop normal limb and tail buds. While chick embryo development proceeded normally over 48 hours with TDP43(wildtype), at 24 hours only 5 to 15% of those embryos expressing mutant TDP43 had reached the normal stage of maturation. TUNEL staining demonstrated a significant increase in the number of apoptotic nuclei in embryos expressing either mutant when compared with wildtype. <a href="#33" class="mim-tip-reference" title="Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J. C., Williams, K. L., Buratti, E., Baralle, F., de Belleroche, J., Mitchell, J. D., Leigh, P. N., Al-Chalabi, A., Miller, C. C., Nicholson, G., Shaw, C. E. <strong>TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis.</strong> Science 319: 1668-1672, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18309045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18309045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18309045[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.1154584" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18309045">Sreedharan et al. (2008)</a> concluded that their results suggested a toxic gain-of-function or dominant-negative effect of mutant TDP43. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18309045" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a Japanese family with ALS previously described by <a href="#35" class="mim-tip-reference" title="Tagawa, A., Tan, C.-F., Kikugawa, K., Fukase, M., Nakano, R., Onodera, O., Nishizawa, M., Takahashi, H. <strong>Familial amyotrophic lateral sclerosis: a SOD1-unrelated Japanese family of bulbar type with Bunina bodies and ubiquitin-positive skein-like inclusions in lower motor neurons.</strong> Acta Neuropath. 113: 205-211, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17036243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17036243</a>] [<a href="https://doi.org/10.1007/s00401-006-0151-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17036243">Tagawa et al. (2007)</a>, <a href="#46" class="mim-tip-reference" title="Yokoseki, A., Shiga, A., Tan, C.-F., Tagawa, A., Kaneko, H., Koyama, A., Eguchi, H., Tsujino, A., Ikeuchi, T., Kakita, A., Okamoto, K., Nishizawa, M., Takahashi, H., Onodera, O. <strong>TDP-43 mutation in familial amyotrophic lateral sclerosis.</strong> Ann. Neurol. 63: 538-542, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18438952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18438952</a>] [<a href="https://doi.org/10.1002/ana.21392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18438952">Yokoseki et al. (2008)</a> identified a heterozygous mutation in the TARDBP gene (Q343R; <a href="#0008">605078.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17036243+18438952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a European family with ALS10, <a href="#15" class="mim-tip-reference" title="Gitcho, M. A., Baloh, R. H., Chakraverty, S., Mayo, K., Norton, J. B., Levitch, D., Hatanpaa, K. J., White, C. L., III., Bigio, E. H., Caselli, R., Baker, M., Al-Lozi, M. T., Morris, J. C., Pestronk, A., Rademakers, R., Goate, A. M., Cairns, N. J. <strong>TDP-43 A315T mutation in familial motor neuron disease.</strong> Ann. Neurol. 63: 535-538, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18288693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18288693</a>] [<a href="https://doi.org/10.1002/ana.21344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18288693">Gitcho et al. (2008)</a> identified a heterozygous mutation in the TARDBP gene (A315T; <a href="#0009">605078.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18288693" 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="Van Deerlin, V. M., Leverenz, J. B., Bekris, L. M., Bird, T. D., Yuan, W., Elman, L. B., Clay, D., Wood, E. M., Chen-Plotkin, A. S., Martinez-Lage, M., Steinbart, E., McCluskey, L., and 11 others. <strong>TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis.</strong> Lancet Neurol. 7: 409-416, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18396105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18396105</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18396105[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/S1474-4422(08)70071-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18396105">Van Deerlin et al. (2008)</a> identified heterozygous mutations in the TARDBP gene (<a href="#0004">605078.0004</a>; <a href="#0005">605078.0005</a>) in affected individuals of 2 unrelated families with autosomal dominant ALS10. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18396105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Kabashi, E., Valdmanis, P. N., Dion, P., Spiegelman, D., McConkey, B. J., Vande Velde, C., Bouchard, J.-P., Lacomblez, L., Pochigaeva, K., Salachas, F., Pradat, P.-F., Camu, W., Meininger, V., Dupre, N., Rouleau, G. A. <strong>TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis.</strong> Nature Genet. 40: 572-574, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18372902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18372902</a>] [<a href="https://doi.org/10.1038/ng.132" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18372902">Kabashi et al. (2008)</a> screened a panel of familial and sporadic ALS cases for TARDBP mutations. They found 8 missense mutations in 9 individuals, 6 from individuals with sporadic ALS and 3 from those with familial ALS, and a concurring increase of a smaller TDP43 product. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18372902" 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 sequence analysis, <a href="#19" class="mim-tip-reference" title="Kabashi, E., Daoud, H., Riviere, J.-B., Valdmanis, P. N., Bourgouin, P., Provencher, P., Pourcher, E., Dion, P., Dupre, N., Rouleau, G. A. <strong>No TARDBP mutations in a French Canadian population of patients with Parkinson disease. (Letter)</strong> Arch. Neurol. 66: 281-282, 2009. Note: Erratum: Arch. Neurol. 66: 432 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19204172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19204172</a>] [<a href="https://doi.org/10.1001/archneurol.2008.568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19204172">Kabashi et al. (2009)</a> did not find any pathogenic mutations in the TARDBP gene among 125 French Canadian patients with dopa-responsive Parkinson disease (PD; <a href="/entry/168600">168600</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19204172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Kuhnlein, P., Sperfeld, A.-D., Vanmassenhove, B., Van Deerlin, V., Lee, V. M.-Y., Trojanowski, J. Q., Kretzschmar, H. A., Ludolph, A. C., Neumann, M. <strong>Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations.</strong> Arch. Neurol. 65: 1185-1189, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18779421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18779421</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18779421[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/10.1001/archneur.65.9.1185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18779421">Kuhnlein et al. (2008)</a> identified mutations in the TARDBP gene in 2 (6.5%) of 31 probands with non-SOD1 familial ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18779421" 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="#22" class="mim-tip-reference" title="Kovacs, G. G., Murrell, J. R., Horvath, S., Haraszti, L., Majtenyi, K., Molnar, M. J., Budka, H., Ghetti, B., Spina, S. <strong>TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea.</strong> Mov. Disord. 24: 1843-1847, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19609911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19609911</a>] [<a href="https://doi.org/10.1002/mds.22697" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19609911">Kovacs et al. (2009)</a> identified a heterozygous mutation in the TARDBP gene (K263E; <a href="#0011">605078.0011</a>) in a Hungarian man with frontotemporal lobar degeneration beginning at age 35 years. He had a rapidly progressive course, resulting in death at age 37., Neurologic examination showed supranuclear gaze palsy, hyperkinetic choreiform movements, motor stereotypies, and primitive reflexes. Motor neuron disease signs, rigidity, and cerebellar ataxia were not present. Phospho-TDP43-immunoreactive deposits were present in neuronal cytoplasmic inclusions in various brain regions, including the cortex, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19609911" 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="Gitcho, M. A., Bigio, E. H., Mishra, M., Johnson, N., Weintraub, S., Mesulam, M., Rademakers, R., Chakraverty, S., Cruchaga, C., Morris, J. C., Goate, A. M., Cairns, N. J. <strong>TARDBP 3-prime-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy.</strong> Acta Neuropath. 118: 633-645, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19618195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19618195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19618195[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/10.1007/s00401-009-0571-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19618195">Gitcho et al. (2009)</a> identified a heterozygous 2076G-A transition in the 3-prime untranslated region of the TARDBP gene (<a href="#0012">605078.0012</a>) in affected members of 2 unrelated families with either ALS10 with or without frontotemporal dementia or FTLD (see <a href="/entry/612069">612069</a>). The first family had 2 mutation carriers with a variable phenotype: the proband was a woman with frontotemporal dementia without motor disease, whereas her brother had lower motor neuron disease without dementia. The father and mother, from whom DNA was not available, had ALS and lower motor neuron disease, respectively, and it was not clear which parent likely transmitted the TARDBP mutation. Neuropathologic analysis of the proband, who did not have motor neuron disease, showed cortical atrophy, neuronal loss in the hippocampus, hippocampal sclerosis, and TDP43-positive neuronal cytoplasmic inclusions in the cortex and hippocampus. The brother's neuropathologic findings were consistent with ALS and showed TDP43-immunoreactivity in the anterior horn cells of the spinal cord and neuronal cytoplasmic inclusions in the hippocampus. The second family included a patient with familial ALS; no neuropathology was available for that patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19618195" 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="#29" 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 6 different missense mutations in the TARDBP gene in 7 (4.3%) of 162 French probands with familial ALS. Three of the families had been previously reported. Patients with TARDBP mutations had disease onset predominantly in the upper limb. One-third of patients had rapid disease progression, two-thirds had a medium disease course, and 1 had a slow disease course. There was evidence of incomplete penetrance. One TARDBP mutation carrier developed frontotemporal dementia 1 year after the onset of motor weakness. <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="#20" class="mim-tip-reference" title="Kabashi, E., Lin, L., Tradewell, M. L., Dion, P. A., Bercier, V., Bourgouin, P., Rochefort, D., Bel Hadj, S., Durham, H. D., Vande Velde, C., Rouleau, G. A., Drapeau, P. <strong>Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo.</strong> Hum. Molec. Genet. 19: 671-683, 2010. Note: Erratum: Hum. Molec. Genet. 19: 3102 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19959528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19959528</a>] [<a href="https://doi.org/10.1093/hmg/ddp534" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19959528">Kabashi et al. (2010)</a> tested the effects of 3 reported TARDBP mutations, A315T, (<a href="#0009">605078.0009</a>), G348C (<a href="#0007">605078.0007</a>), and A382T (<a href="#0013">605078.0013</a>), in cell lines, primary cultured motor neurons, and living zebrafish embryos. Each of the 3 mutants and wildtype human TDP43 localized to nuclei when expressed in COS-1 and Neuro2A cells by transient transfection. However, when expressed in motor neurons from dissociated spinal cord cultures, these mutant TARDBP alleles were neurotoxic, concomitant with perinuclear localization and aggregation of TDP43. Overexpression of mutant human TARDBP caused a motor phenotype in zebrafish embryos consisting of shorter motor neuronal axons, premature and excessive branching, as well as swimming deficits. Knockdown of zebrafish Tardbp led to a similar phenotype, which was rescued by coexpressing wildtype but not mutant human TARDBP. <a href="#20" class="mim-tip-reference" title="Kabashi, E., Lin, L., Tradewell, M. L., Dion, P. A., Bercier, V., Bourgouin, P., Rochefort, D., Bel Hadj, S., Durham, H. D., Vande Velde, C., Rouleau, G. A., Drapeau, P. <strong>Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo.</strong> Hum. Molec. Genet. 19: 671-683, 2010. Note: Erratum: Hum. Molec. Genet. 19: 3102 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19959528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19959528</a>] [<a href="https://doi.org/10.1093/hmg/ddp534" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19959528">Kabashi et al. (2010)</a> suggested that both a toxic gain of function as well as a novel loss of function may be involved in the molecular mechanism by which mutant TDP43 contributes to disease pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19959528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#11" class="mim-tip-reference" title="Corcia, P., Valdmanis, P., Millecamps, S., Lionnet, C., Blasco, H., Mouzat, K., Daoud, H., Belzil, V., Morales, R., Pageot, N., Danel-Brunaud, V., Vandenberghe, N., Pradat, P. F., Couratier, P., Salachas, F., Lumbroso, S., Rouleau, G. A., Meininger, V., Camu, W. <strong>Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations.</strong> Neurology 78: 1519-1526, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22539580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22539580</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182553c88" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22539580">Corcia et al. (2012)</a> identified 19 patients from 9 families with ALS10 and 9 patients with apparently sporadic ALS10. The patients were French, and all carried mutations in the TARDBP gene. The mean age at onset was 53.4 years, and the upper limb was the most common site of onset. Only 2 patients had dementia. The median disease duration was 63 months; 2 patients were alive after 8 years. These patients were pooled with 117 ALS10 patients reported in the literature. Among all those with TARDBP mutations, Caucasians tended to have upper limb onset, while Asians tended to have bulbar onset. The G298S mutation (<a href="#0005">605078.0005</a>) was associated with the shortest survival, whereas A315T (<a href="#0009">605078.0009</a>) and M337V (<a href="#0001">605078.0001</a>) were associated with longest duration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22539580" 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 expression of 7 pathogenic ALS-associated mutant TDP43 proteins (e.g., M337V, <a href="#0001">605078.0001</a>; A382T, <a href="#0013">605078.0013</a>; G298S, <a href="#0005">605078.0005</a>; G348C, <a href="#0007">605078.0007</a>; Q343R, <a href="#0008">605078.0008</a>; and A315T, <a href="#0009">605078.0009</a>) in a differentiated neuronal cell line, <a href="#41" class="mim-tip-reference" title="Watanabe, S., Kaneko, K., Yamanaka, K. <strong>Accelerated disease onset with stabilized familial amyotrophic lateral sclerosis (ALS)-linked mutant TDP-43 proteins.</strong> J. Biol. Chem. 288: 3641-3654, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23235148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23235148</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23235148[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.M112.433615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23235148">Watanabe et al. (2013)</a> found that all had consistently longer half-lives compared to the wildtype protein. Patients carrying mutations with longer half-lives showed earlier disease onset (p = 0.00252), although there was no correlation between protein half-lives and disease duration. Proteins with mutations in the nuclear export signal had an extremely long half-life, whereas a second group of mutations generated within the nuclear localization signal were less stable than wildtype. In additional studies, most of 18 ALS-linked mutant TDP43 proteins showed lower solubility to the detergent Sarkosyl compared to wildtype. A cell model in which wildtype TDP43 was stabilized caused cytotoxicity, nuclear accumulation, insolubility, proteasomal impairment with increased numbers of misfolded C-terminal cleaved TDP43 products, and dysregulation of normal mRNA processing. The findings suggested that increased stability of either wildtype or mutant TDP43 can cause a gain of toxicity through abnormal proteostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23235148" 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="#42" class="mim-tip-reference" title="Wegorzewska, I., Bell, S., Cairns, N. J., Miller, T. M., Baloh, R. H. <strong>TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration.</strong> Proc. Nat. Acad. Sci. 106: 18809-18814, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19833869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19833869</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19833869[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0908767106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19833869">Wegorzewska et al. (2009)</a> found that transgenic mice expressing a Tdp43 A315T mutation (<a href="#0009">605078.0009</a>) developed progressive gait abnormalities at about 3 to 4 months of age and died at about 5 months of age. Postmortem examination showed accumulation of ubiquitinated proteins selectively in the cytoplasm of neurons in cortical layer 5, including the motor cortex. The inclusions did not stain for TDP43, but the changes were associated with neuronal loss and increased glial reaction. Examination of the spinal cord of mutant mice showed degeneration of descending motor axons and ubiquitin pathology in large neurons of the ventral horn; there was also loss of motor neurons. Mutant mice also showed Tdp43 C-terminal fragments in the brain and spinal cord prior to the onset of gait abnormalities. <a href="#42" class="mim-tip-reference" title="Wegorzewska, I., Bell, S., Cairns, N. J., Miller, T. M., Baloh, R. H. <strong>TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration.</strong> Proc. Nat. Acad. Sci. 106: 18809-18814, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19833869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19833869</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19833869[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0908767106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19833869">Wegorzewska et al. (2009)</a> concluded that since cytoplasmic Tdp43 aggregates were not present in mutant mice, they are not required for neurodegeneration. These results indicated that the selective neuronal vulnerability in Tdp43-related neurodegeneration is related to altered DNA/RNA-binding protein function rather than to toxic aggregation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19833869" 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 translating ribosome affinity purification and microarray analysis, <a href="#28" class="mim-tip-reference" title="MacNair, L., Xiao, S., Miletic, D., Ghani, M., Julien, J.-P., Keith, J., Zinman, L., Rogaeva, E., Robertson, J. <strong>MTHFSD and DDX58 are novel RNA-binding proteins abnormally regulated in amyotrophic lateral sclerosis.</strong> Brain 139: 86-100, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26525917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26525917</a>] [<a href="https://doi.org/10.1093/brain/awv308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26525917">MacNair et al. (2016)</a> found that several mRNAs were abnormally regulated in 10-month-old symptomatic Tdp43 A315T transgenic mice compared with wildtype controls and 5-month-old presymptomatic Tdp43 A315T mice. Those upregulated over 2-fold in older Tdp43 A315T mice included Ccl4 (<a href="/entry/182284">182284</a>), Tdp43, Pkib (<a href="/entry/606914">606914</a>), and Ddx58 (<a href="/entry/609631">609631</a>), and those downregulated included Prickle4 (<a href="/entry/611389">611389</a>), Pes1 (<a href="/entry/605819">605819</a>), and Mthfsd (<a href="/entry/616820">616820</a>). Expression of DDX58 and MTHFSD was similarly misregulated in human ALS motor neurons, and RNA immunoprecipitation analysis showed that Mthfsd and Ddx58 were direct targets of Tdp43 in transfected mouse neuroblastoma cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26525917" 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="Tsai, K.-J., Yang, C.-H., Fang, Y.-H., Cho, K.-H., Chien, W.-L., Wang, W.-T., Wu, T.-W., Lin, C.-P., Fu, W.-M., Shen, C.-K. J. <strong>Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U.</strong> J. Exp. Med. 207: 1661-1673, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20660618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20660618</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20660618[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/10.1084/jem.20092164" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20660618">Tsai et al. (2010)</a> generated an FTLDU mouse model by transgenically overexpressing Tdp43 in forebrain. Transgenic mice exhibited impaired learning and memory, progressive motor dysfunction, and hippocampal atrophy. The impairments were accompanied by reduced levels of phosphorylated Erk (see MAPK1; <a href="/entry/176948">176948</a>) and phosphorylated Creb (CREB1; <a href="/entry/123810">123810</a>) and increased levels of gliosis in the brains of transgenic mice. Cells with Tdp43-positive, ubiquitin-positive neuronal cytoplasmic inclusions (NCIs) and Tdp43-deleted nuclei appeared in transgenic mouse brains in an age-dependent manner. <a href="#37" class="mim-tip-reference" title="Tsai, K.-J., Yang, C.-H., Fang, Y.-H., Cho, K.-H., Chien, W.-L., Wang, W.-T., Wu, T.-W., Lin, C.-P., Fu, W.-M., Shen, C.-K. J. <strong>Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U.</strong> J. Exp. Med. 207: 1661-1673, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20660618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20660618</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20660618[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/10.1084/jem.20092164" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20660618">Tsai et al. (2010)</a> concluded that increased levels of TDP43 protein in forebrain are sufficient to lead to formation of TDP43-positive, ubiquitin-positive NCIs and neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20660618" 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>Independently, <a href="#43" class="mim-tip-reference" title="Wils, H., Kleinberger, G., Janssens, J., Pereson, S., Joris, G., Cuijt, I., Smits, V., Ceuterick-de Groote, C., Van Broeckhoven, C., Kumar-Singh, S. <strong>TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration.</strong> Proc. Nat. Acad. Sci. 107: 3858-3863, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20133711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20133711</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20133711[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0912417107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20133711">Wils et al. (2010)</a> observed neurodegeneration in transgenic mice overexpressing wildtype human TDP43. Homozygous and hemizygous transgenic mice showed dose-dependent degeneration of cortical and spinal motor neurons and developed spastic quadriplegia similar to ALS. Transgenic mice also developed dose-dependent degeneration of nonmotor cortical and subcortical neurons characteristic of FTLD. Affected neurons of the spinal cord and brain showed nuclear and cytoplasmic aggregates of ubiquitinated and phosphorylated TDP43. The characteristic, approximately 25-kD TDP43 C-terminal fragments were also recovered from nuclear fractions and correlated with disease development and progression in transgenic mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20133711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Ash, P. E. A., Zhang, Y.-J., Roberts, C. M., Saldi, T., Hutter, H., Buratti, E., Petrucelli, L., Link, C. D. <strong>Neurotoxic effects of TDP-43 overexpression in C. elegans.</strong> Hum. Molec. Genet. 19: 3206-3218, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20530643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20530643</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20530643[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/ddq230" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20530643">Ash et al. (2010)</a> engineered panneuronal expression of human TDP43 in C. elegans to generate an in vivo model of TDP43 function and neurotoxicity. Transgenic worms with neuronal expression of human TDP43 exhibited an 'uncoordinated' phenotype and had abnormal motoneuron synapses. C. elegans contains a single putative ortholog of TDP43, designated tdp1, which could support alternative splicing of CFTR (<a href="/entry/602421">602421</a>) in a cell-based assay. Neuronal overexpression of tdp1 also resulted in an uncoordinated phenotype, whereas deletion of the tdp1 gene did not affect movement or alter motoneuron synapses. Wildtype human TDP43 expressed in C. elegans localized to the nucleus. TDP43 mutants missing either RNA recognition domain RRM1 or RRM2 completely blocked neurotoxicity, as did a mutant missing its C-terminal domain. These TDP43 mutants still accumulated in the nucleus, although their subnuclear distribution was altered. Fusion of the tdp1 C-terminal domain to a TDP43 N terminus restored normal subnuclear localization and toxicity in C. elegans and CFTR splicing in cell-based assays. Overexpression of wildtype TDP43 in differentiated M17 cells also resulted in cell toxicity. <a href="#3" class="mim-tip-reference" title="Ash, P. E. A., Zhang, Y.-J., Roberts, C. M., Saldi, T., Hutter, H., Buratti, E., Petrucelli, L., Link, C. D. <strong>Neurotoxic effects of TDP-43 overexpression in C. elegans.</strong> Hum. Molec. Genet. 19: 3206-3218, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20530643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20530643</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20530643[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/ddq230" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20530643">Ash et al. (2010)</a> concluded that overexpression of wildtype TDP43 is sufficient to induce neurotoxicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20530643" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Diaper, D. C., Adachi, Y., Sutcliffe, B., Humphrey, D. M., Elliott, C. J. H., Stepto, A., Ludlow, Z. N., Vanden Broeck, L., Callaerts, P., Dermaut, B., Al-Chalabi, A., Shaw, C. E., Robinson, I. M., Hirth, F. <strong>Loss and gain of Drosophila TDP-43 impair synaptic efficacy and motor control leading to age-related neurodegeneration by loss-of-function phenotypes.</strong> Hum. Molec. Genet. 22: 1539-1557, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23307927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23307927</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23307927[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/ddt005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23307927">Diaper et al. (2013)</a> found that deletion of the TAR DNA-binding protein homolog (Tbph) in Drosophila caused impaired synaptic transmission at the larval and adult neuromuscular junction. Impaired presynaptic transmission was the earliest Tbph-related defect. Overexpression of Tbph in adults also resulted in synaptic defects and age-related progressive degeneration of neurons involved in motor control. Progressive neurodegeneration was also seen with inactivated Tbph. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23307927" 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="Taylor, L. M., McMillan, P. J., Liachko, N. F., Strovas, T. J., Ghetti, B., Bird, T. D., Keene, C. D., Kraemer, B. C. <strong>Pathological phosphorylation of tau and TDP-43 by TTBK1 and TTBK2 drives neurodegeneration.</strong> Molec. Neurodegener. 13: 7, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29409526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29409526</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29409526[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/10.1186/s13024-018-0237-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29409526">Taylor et al. (2018)</a> showed that transgenic C. elegans expressing the kinase catalytic domain of human TTBK1 or TTBK2 were behaviorally normal. However, coexpression of TTBK1, but not TTBK2, with TDP43 led to behavioral abnormalities and increased phosphorylation of TDP43. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29409526" 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 an English family segregating autosomal dominant amyotrophic lateral sclerosis without frontotemporal dementia (<a href="/entry/612069">612069</a>), <a href="#33" class="mim-tip-reference" title="Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J. C., Williams, K. L., Buratti, E., Baralle, F., de Belleroche, J., Mitchell, J. D., Leigh, P. N., Al-Chalabi, A., Miller, C. C., Nicholson, G., Shaw, C. E. <strong>TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis.</strong> Science 319: 1668-1672, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18309045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18309045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18309045[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.1154584" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18309045">Sreedharan et al. (2008)</a> identified an A-to-G transition at nucleotide 1009 in exon 6 of the TARDBP gene, resulting in a methionine-to-valine substitution at codon 337 (M337V). Methionine at this position is invariant in human, orangutan, mouse, opossum, chicken, frog, and zebrafish. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18309045" 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">rs80356727 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356727;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=rs80356727" 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=rs80356727" 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=RCV000005540" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005540" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005540</a>
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<p>In a 72-year-old Caucasian British man who developed limb-onset ALS (<a href="/entry/612069">612069</a>) with a disease duration of 3 years, <a href="#33" class="mim-tip-reference" title="Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J. C., Williams, K. L., Buratti, E., Baralle, F., de Belleroche, J., Mitchell, J. D., Leigh, P. N., Al-Chalabi, A., Miller, C. C., Nicholson, G., Shaw, C. E. <strong>TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis.</strong> Science 319: 1668-1672, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18309045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18309045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18309045[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.1154584" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18309045">Sreedharan et al. (2008)</a> identified a C-to-A transversion at nucleotide 991 in exon 6 of the TARDBP gene, resulting in a glutamine-to-lysine substitution at codon 331 (Q331K). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18309045" 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 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</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> rs80356721 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356721;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/rs80356721?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=rs80356721" 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=rs80356721" 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=RCV000005541 OR RCV002371764" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005541, RCV002371764" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005541...</a>
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<p>In an Australian man who developed limb-onset ALS (<a href="/entry/612069">612069</a>) at age 65 with a disease duration of 5 years and no atypical features, <a href="#33" class="mim-tip-reference" title="Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J. C., Williams, K. L., Buratti, E., Baralle, F., de Belleroche, J., Mitchell, J. D., Leigh, P. N., Al-Chalabi, A., Miller, C. C., Nicholson, G., Shaw, C. E. <strong>TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis.</strong> Science 319: 1668-1672, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18309045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18309045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18309045[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.1154584" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18309045">Sreedharan et al. (2008)</a> identified a G-to-C transversion at nucleotide 881 in exon 6 of the TARDBP gene, resulting in a glycine-to-alanine substitution at codon 294 (G294A). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18309045" 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="#26" class="mim-tip-reference" title="Luquin, N., Yu, B., Saunderson, R. B., Trent, R. J., Pamphlett, R. <strong>Genetic variants in the promoter of TARDBP in sporadic amyotrophic lateral sclerosis.</strong> Neuromusc. Disord. 19: 696-700, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19695877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19695877</a>] [<a href="https://doi.org/10.1016/j.nmd.2009.07.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19695877">Luquin et al. (2009)</a> identified the G294A mutation in postmortem brain tissue from a patient with sporadic ALS. No clinical information was given. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19695877" 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 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</strong>
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TARDBP, GLY290ALA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908395 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908395;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=rs121908395" 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=rs121908395" 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=RCV000005542 OR RCV001054737" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005542, RCV001054737" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005542...</a>
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<p>In a Caucasian father and daughter with autosomal dominant ALS10 (<a href="/entry/612069">612069</a>), <a href="#38" class="mim-tip-reference" title="Van Deerlin, V. M., Leverenz, J. B., Bekris, L. M., Bird, T. D., Yuan, W., Elman, L. B., Clay, D., Wood, E. M., Chen-Plotkin, A. S., Martinez-Lage, M., Steinbart, E., McCluskey, L., and 11 others. <strong>TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis.</strong> Lancet Neurol. 7: 409-416, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18396105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18396105</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18396105[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/S1474-4422(08)70071-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18396105">Van Deerlin et al. (2008)</a> identified a heterozygous 869G-C transversion in exon 6 of the TARDBP gene, resulting in a gly290-to-ala (G290A) substitution in the C-terminal region of TDP43. The mutation was not identified in 747 white controls. The daughter presented with dysarthria and dysphagia at age 51 years and had a rapidly progressive course involving the limbs and respiration. She died after 13 months. Her father had presented with arm weakness at age 47 years and died after 16 months. Postmortem examination showed findings consistent with ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18396105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</strong>
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TARDBP, GLY298SER
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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> rs4884357 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4884357;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/rs4884357?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=rs4884357" 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=rs4884357" 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=RCV000005543 OR RCV000713825 OR RCV001851670 OR RCV004754243" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005543, RCV000713825, RCV001851670, RCV004754243" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005543...</a>
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<p>In affected members of a Chinese family with autosomal dominant ALS10 (<a href="/entry/612069">612069</a>), <a href="#38" class="mim-tip-reference" title="Van Deerlin, V. M., Leverenz, J. B., Bekris, L. M., Bird, T. D., Yuan, W., Elman, L. B., Clay, D., Wood, E. M., Chen-Plotkin, A. S., Martinez-Lage, M., Steinbart, E., McCluskey, L., and 11 others. <strong>TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis.</strong> Lancet Neurol. 7: 409-416, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18396105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18396105</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18396105[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/S1474-4422(08)70071-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18396105">Van Deerlin et al. (2008)</a> identified a heterozygous 892G-A transition in exon 6 of the TARDBP gene, resulting in a gly298-to-ser (G298S) substitution in the C-terminal region of TDP43. The mutation was not identified in 747 white controls or 380 Chinese controls. Five patients in 2 generations were affected with onset between ages 41 and 60 years. Most showed rapid progression with death within 1 or 2 years. Postmortem examination of 2 patients showed changes consistent with ALS as well as TDP43-positive inclusions in upper and lower motor neurons and in various brain regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18396105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</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">rs80356717 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356717;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=rs80356717" 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=rs80356717" 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=RCV000005544" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005544" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005544</a>
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<p>In a 56-year-old female with amyotrophic lateral sclerosis (<a href="/entry/612069">612069</a>), <a href="#21" class="mim-tip-reference" title="Kabashi, E., Valdmanis, P. N., Dion, P., Spiegelman, D., McConkey, B. J., Vande Velde, C., Bouchard, J.-P., Lacomblez, L., Pochigaeva, K., Salachas, F., Pradat, P.-F., Camu, W., Meininger, V., Dupre, N., Rouleau, G. A. <strong>TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis.</strong> Nature Genet. 40: 572-574, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18372902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18372902</a>] [<a href="https://doi.org/10.1038/ng.132" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18372902">Kabashi et al. (2008)</a> found a heterozygous A-to-G transition in exon 4 of the TARDBP gene (640A-G) that resulted in an asp169-to-gly substitution (D169G) in TDP43. The mutation occurred in the first RNA recognition motif (RRM1) and was predicted to abrogate RNA binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18372902" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</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">rs80356733 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356733;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=rs80356733" 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=rs80356733" 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=RCV000005545 OR RCV000516886 OR RCV001851671" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005545, RCV000516886, RCV001851671" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005545...</a>
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<p>In a 30-year-old female patient with amyotrophic lateral sclerosis (<a href="/entry/612069">612069</a>), <a href="#21" class="mim-tip-reference" title="Kabashi, E., Valdmanis, P. N., Dion, P., Spiegelman, D., McConkey, B. J., Vande Velde, C., Bouchard, J.-P., Lacomblez, L., Pochigaeva, K., Salachas, F., Pradat, P.-F., Camu, W., Meininger, V., Dupre, N., Rouleau, G. A. <strong>TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis.</strong> Nature Genet. 40: 572-574, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18372902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18372902</a>] [<a href="https://doi.org/10.1038/ng.132" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18372902">Kabashi et al. (2008)</a> detected a heterozygous G-to-T transversion at nucleotide 1176 in exon 6 of the TARDBP gene that resulted in substitution of cys for gly at codon 348 of TDP43 (G348C). The mutation, which introduced a cysteine to the C-terminal hnRNP interaction region, was predicted to increase the propensity for aggregation through the formation of intermolecular disulfide bridges. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18372902" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Kuhnlein, P., Sperfeld, A.-D., Vanmassenhove, B., Van Deerlin, V., Lee, V. M.-Y., Trojanowski, J. Q., Kretzschmar, H. A., Ludolph, A. C., Neumann, M. <strong>Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations.</strong> Arch. Neurol. 65: 1185-1189, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18779421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18779421</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18779421[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/10.1001/archneur.65.9.1185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18779421">Kuhnlein et al. (2008)</a> identified the G348C mutation in affected members of a German family with ALS10. The proband presented at age 55 years with paresis of the right hand, which progressed rapidly to involve the arms and lower limbs and left her wheelchair-bound within 2.5 years. She died of respiratory insufficiency 3 years after disease onset. The patient's mother had died of respiratory insufficiency due to a similar disorder. There were no clinically relevant bulbar symptoms and no cognitive impairment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18779421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</strong>
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TARDBP, GLN343ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80356731 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356731;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=rs80356731" 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=rs80356731" 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=RCV000005546" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005546" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005546</a>
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<p>In affected members of a Japanese family with amyotrophic lateral sclerosis (<a href="/entry/612069">612069</a>), <a href="#46" class="mim-tip-reference" title="Yokoseki, A., Shiga, A., Tan, C.-F., Tagawa, A., Kaneko, H., Koyama, A., Eguchi, H., Tsujino, A., Ikeuchi, T., Kakita, A., Okamoto, K., Nishizawa, M., Takahashi, H., Onodera, O. <strong>TDP-43 mutation in familial amyotrophic lateral sclerosis.</strong> Ann. Neurol. 63: 538-542, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18438952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18438952</a>] [<a href="https://doi.org/10.1002/ana.21392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18438952">Yokoseki et al. (2008)</a> identified heterozygosity for a 1028A-G transition in the TARDBP gene, resulting in a gln343-to-arg (Q343R) substitution. The mutation occurs in a highly conserved residue and was not present in 534 chromosomes in Japanese control subjects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18438952" 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 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</strong>
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TARDBP, ALA315THR
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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> rs80356726 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356726;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/rs80356726?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=rs80356726" 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=rs80356726" 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=RCV000005547 OR RCV001384596 OR RCV004546411" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005547, RCV001384596, RCV004546411" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005547...</a>
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<p>In affected members of a European family with amyotrophic lateral sclerosis (<a href="/entry/612069">612069</a>), <a href="#15" class="mim-tip-reference" title="Gitcho, M. A., Baloh, R. H., Chakraverty, S., Mayo, K., Norton, J. B., Levitch, D., Hatanpaa, K. J., White, C. L., III., Bigio, E. H., Caselli, R., Baker, M., Al-Lozi, M. T., Morris, J. C., Pestronk, A., Rademakers, R., Goate, A. M., Cairns, N. J. <strong>TDP-43 A315T mutation in familial motor neuron disease.</strong> Ann. Neurol. 63: 535-538, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18288693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18288693</a>] [<a href="https://doi.org/10.1002/ana.21344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18288693">Gitcho et al. (2008)</a> identified heterozygosity for a 1077G-A transition in exon 6 of the TARDBP gene, resulting in an ala315-to-thr substitution. The mutation occurs in a highly conserved residue and was not found in 1,505 ethnically matched elderly control subjects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18288693" 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 10 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</strong>
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TARDBP, GLY295SER
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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> rs80356723 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356723;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/rs80356723?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=rs80356723" 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=rs80356723" 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=RCV000020674 OR RCV003764615" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020674, RCV003764615" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020674...</a>
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<p>In a woman with ALS10 (<a href="/entry/612069">612069</a>), <a href="#5" class="mim-tip-reference" title="Benajiba, L., Le Ber, I., Camuzat, A., Lacoste, M., Thomas-Anterion, C., Couratier, P., Legallic, S., Salachas, F., Hannequin, D., Decousus, M., Lacomblez, L., Guedj, E., Golfier, V., Camu, W., Dubois, B., Campion, D., Meininger, V., Brice, A., French Clinical and Genetic Research Network on Frontotemporal Lobar Degeneration/Frontotemporal Lobar Degeneration with Motoneuron Disease. <strong>TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration.</strong> Ann. Neurol. 65: 470-474, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19350673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19350673</a>] [<a href="https://doi.org/10.1002/ana.21612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19350673">Benajiba et al. (2009)</a> identified a heterozygous 883G-A transition in exon 6 of the TARDBP gene, resulting in a gly295-to-ser (G295S) substitution in the hnRNP-binding domain. She also developed semantic frontotemporal dementia. Her sister, who carried the mutation, and their deceased father, who presumably carried the mutation, both had motor neuron disease without dementia. The G295S mutation was also identified in an unrelated woman with the behavioral variant of frontotemporal dementia and motor neuron disease. The mutation was not found in 400 control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19350673" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<strong>.0011 FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, TARDBP-RELATED</strong>
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TARDBP, LYS263GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267607102 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607102;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=rs267607102" 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=rs267607102" 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=RCV000005549" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005549" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005549</a>
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<p>In a Hungarian man with frontotemporal lobar degeneration (see <a href="/entry/612069">612069</a>), <a href="#22" class="mim-tip-reference" title="Kovacs, G. G., Murrell, J. R., Horvath, S., Haraszti, L., Majtenyi, K., Molnar, M. J., Budka, H., Ghetti, B., Spina, S. <strong>TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea.</strong> Mov. Disord. 24: 1843-1847, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19609911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19609911</a>] [<a href="https://doi.org/10.1002/mds.22697" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19609911">Kovacs et al. (2009)</a> identified a heterozygous A-to-G transition in exon 6 of the TARDBP gene, resulting in a lys263-to-glu (K263E) substitution in the highly conserved C terminus. The mutation was not found in 530 controls. The patient developed personality changes beginning at age 35 years. This was followed by a rapid deterioration in attention and thinking, with psychomotor agitation and insomnia, consistent with FTD. Neurologic examination showed supranuclear gaze palsy, hyperkinetic choreiform movements, motor stereotypies, and primitive reflexes. Motor neuron disease signs, rigidity, and cerebellar ataxia were not present. He died at age 37 years of pulmonary edema secondary to cardiac failure. Neuropathologic examination neuronal loss and astrogliosis in the subcortical gray matter. Phospho-TDP43-immunoreactive deposits were present in neuronal cytoplasmic inclusions in various brain regions, including the cortex, basal ganglia, thalamus, and brainstem. The findings indicated that TARDBP mutations can be associated with a wider clinicopathologic spectrum of disorders than originally thought. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19609911" 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 AMYOTROPHIC LATERAL SCLEROSIS 10 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</strong>
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FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, TARDBP-RELATED, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906334 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906334;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=rs387906334" 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=rs387906334" 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=RCV000005550 OR RCV000005551 OR RCV002512811" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005550, RCV000005551, RCV002512811" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005550...</a>
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<p>In affected members of 2 unrelated families with either ALS10 with or without frontotemporal dementia (<a href="/entry/612069">612069</a>) or FTLD (see <a href="/entry/612069">612069</a>), <a href="#16" class="mim-tip-reference" title="Gitcho, M. A., Bigio, E. H., Mishra, M., Johnson, N., Weintraub, S., Mesulam, M., Rademakers, R., Chakraverty, S., Cruchaga, C., Morris, J. C., Goate, A. M., Cairns, N. J. <strong>TARDBP 3-prime-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy.</strong> Acta Neuropath. 118: 633-645, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19618195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19618195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19618195[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/10.1007/s00401-009-0571-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19618195">Gitcho et al. (2009)</a> identified a heterozygous 2076G-A transition in the 3-prime untranslated region of the TARDBP gene adjacent to the last exon, exon 6. The first family had 2 mutation carriers with a variable phenotype: the proband was a woman with frontotemporal dementia without motor disease, whereas her brother had lower motor neuron disease without dementia. The father and mother, from whom DNA was not available, had ALS and lower motor neuron disease, respectively, and it was not clear which parent likely transmitted the TARDBP mutation. Neuropathologic analysis of the proband, who did not have motor neuron disease, showed cortical atrophy, neuronal loss in the hippocampus, hippocampal sclerosis, and TDP43-positive neuronal cytoplasmic inclusions in the cortex and hippocampus. There was no evidence of motor neuron loss from the motor nuclei of the brainstem. The brother's neuropathologic findings were consistent with ALS and showed TDP43-immunoreactivity in the anterior horn cells of the spinal cord and neuronal cytoplasmic inclusions in the hippocampus. The second family included a patient with familial ALS; no neuropathology was available for that patient. The 2076G-A variant is highly conserved across species, suggesting functional importance, and was not found in 974 control individuals. Allele-specific functional analysis showed that the 2076G-A variant was associated with a 2-fold increase in TARDBP expression. These findings suggested that a common molecular pathology can result in clinically heterogeneous phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19618195" 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>.0013 AMYOTROPHIC LATERAL SCLEROSIS 10 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</strong>
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FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, TARDBP-RELATED, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs367543041 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs367543041;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/rs367543041?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=rs367543041" 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=rs367543041" 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=RCV000020663 OR RCV000106321 OR RCV000413910 OR RCV002513146 OR RCV003944833" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020663, RCV000106321, RCV000413910, RCV002513146, RCV003944833" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020663...</a>
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<p><strong><em>Amyotrophic Lateral Sclerosis 10</em></strong></p><p>
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In 7 Italian probands with ALS10 (<a href="/entry/612069">612069</a>), <a href="#12" class="mim-tip-reference" title="Corrado, L., Ratti, A., Gellera, C., Buratti, E., Castellotti, B., Carlomagno, Y., Ticozzi, N., Mazzini, L., Testa, L., Taroni, F., Baralle, F. E., Silani, V., D'Alfonso, S. <strong>High frequency of TARDBP gene mutations in Italian patients with amyotrophic lateral sclerosis.</strong> Hum. Mutat. 30: 688-694, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19224587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19224587</a>] [<a href="https://doi.org/10.1002/humu.20950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19224587">Corrado et al. (2009)</a> identified a heterozygous 1144G-A transition in exon 6 of the TARDBP gene, resulting in an ala382-to-thr (A382T) substitution. The patients were identified from a larger cohort of 666 Italian ALS patients. A382T was the most common of all TARDBP mutations and was found in 6 of 18 probands. All the patients had ALS with predominantly lower motor neuron disease affecting the upper limb, with proximal spreading; none had cognitive impairment. Haplotype analysis indicated a founder effect in 5 of 7 patients with the A382T mutation. Lymphocyte studies showed accumulation of aberrant TARDBP bands, suggesting instability of the mutant protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19224587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Chio, A., Calvo, A., Moglia, C., Restagno, G., Ossola, I., Brunetti, M., Montuschi, A., Cistaro, A., Ticca, A., Traynor, B. J., Schymick, J. C., Mutani, R., Marrosu, M. G., Murru, M. R., Borghero, G. <strong>Amyotrophic lateral sclerosis-frontotemporal lobar dementia in 3 families with p.Ala382Thr TARDBP mutations.</strong> Arch. Neurol. 67: 1002-1009, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20697052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20697052</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20697052[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/10.1001/archneurol.2010.173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20697052">Chio et al. (2010)</a> identified a heterozygous A382T mutation in affected members of 3 unrelated Italian families with ALS10 with frontotemporal dementia (<a href="/entry/612069">612069</a>). The mutation was not found in over 1,200 controls. Affected individuals developed rapidly progressive muscle atrophy and weakness associated with hyperreflexia, dysarthria, dysphagia, and respiratory insufficiency between ages 25 and 78 years. Frontotemporal dementia, characterized by disinhibition, emotional lability, apathy, and executive dysfunction, developed soon after the onset of ALS. One mutation carrier did not manifest neurologic symptoms at age 65 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20697052" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Chio, A., Borghero, G., Pugliatti, M., Ticca, A., Calvo, A., Moglia, C., Mutani, R., Brunetti, M., Ossola, I., Marrosu, M. G., Murru, M. R., Floris, G., and 12 others. <strong>Large proportion of amyotrophic lateral sclerosis cases in Sardinia due to a single founder mutation of the TARDBP gene.</strong> Arch. Neurol. 68: 594-598, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21220647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21220647</a>] [<a href="https://doi.org/10.1001/archneurol.2010.352" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21220647">Chio et al. (2011)</a> identified the A382T mutation in 39 (28.7%) of 135 Sardinian patients with ALS, including 15 with familial disease and 24 with apparently sporadic disease. None of 156 ethnically matched controls carried the mutation. Haplotype analysis of 5 patients with the mutation identified a 94-SNP common risk haplotype spanning 663 kb across the TARDBP locus on chromosome 1p36.22. The findings suggested a founder effect in this population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21220647" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Frontotemporal Dementia</em></strong></p><p>
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<a href="#34" class="mim-tip-reference" title="Synofzik, M., Born, C., Rominger, A., Lummel, N., Schols, L., Biskup, S., Schule, C., Grasshoff, U., Klopstock, T., Adamczyk, C. <strong>Targeted high-throughput sequencing identifies a TARDBP mutation as a cause of early-onset FTD without motor neuron disease.</strong> Neurobiol. Aging 35: 1212.e1-5, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24300238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24300238</a>] [<a href="https://doi.org/10.1016/j.neurobiolaging.2013.10.092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24300238">Synofzik et al. (2014)</a> identified a heterozygous A382T mutation in a Sardinian man with behavioral variant frontotemporal dementia without motor signs (see <a href="/entry/612069">612069</a>). The patient developed rapidly progressive dementia beginning at age 31, and was severely disabled with no meaningful communication or social interaction by age 37. Brain MRI showed generalized cerebral atrophy, particularly in the anterior temporal lobe and hippocampi. The patient had no evidence of ALS. His father, who was likely a carrier based on family history, did not show signs of dementia or ALS at age 63 years. Family history was positive for ALS without dementia in 2 individuals in antecedent generations; DNA was not available from these patients. The mutation was found by massively parallel sequencing of the proband and confirmed by Sanger sequencing. The findings confirmed that TARDBP mutations can cause a pure dementia phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24300238" 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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Arai, T., Hasegawa, M., Akiyama, H., Ikeda, K., Nonaka, T., Mori, H., Mann, D., Tsuchiya, K., Yoshida, M., Hashizume, Y., Oda, T.
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<strong>TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.</strong>
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Biochem. Biophys. Res. Commun. 351: 602-611, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17084815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17084815</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17084815" 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.bbrc.2006.10.093" target="_blank">Full Text</a>]
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Armakola, M., Higgins, M. J., Figley, M. D., Barmada, S. J., Scarborough, E. A., Diaz, Z., Fang, X., Shorter, J., Krogan, N. J., Finkbeiner, S., Farese, R. V., Jr., Gitler, A. D.
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<strong>Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models.</strong>
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Nature Genet. 44: 1302-1309, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23104007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23104007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23104007[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=23104007" 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/ng.2434" target="_blank">Full Text</a>]
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Ash, P. E. A., Zhang, Y.-J., Roberts, C. M., Saldi, T., Hutter, H., Buratti, E., Petrucelli, L., Link, C. D.
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<strong>Neurotoxic effects of TDP-43 overexpression in C. elegans.</strong>
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Hum. Molec. Genet. 19: 3206-3218, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20530643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20530643</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20530643[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=20530643" 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/ddq230" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature22038" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.21612" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M104236200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/420978" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/emboj/20.7.1774" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneurol.2010.352" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneurol.2010.173" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e3182553c88" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20950" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddt005" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.21344" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/s41586-024-07042-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneurol.2008.568" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp534" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng.132" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/mds.22697" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.65.9.1185" 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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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18309045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18309045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18309045[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=18309045" 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.1154584" target="_blank">Full Text</a>]
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<a id="Synofzik2014" class="mim-anchor"></a>
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<div class="">
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Synofzik, M., Born, C., Rominger, A., Lummel, N., Schols, L., Biskup, S., Schule, C., Grasshoff, U., Klopstock, T., Adamczyk, C.
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<strong>Targeted high-throughput sequencing identifies a TARDBP mutation as a cause of early-onset FTD without motor neuron disease.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24300238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24300238</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24300238" 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.neurobiolaging.2013.10.092" target="_blank">Full Text</a>]
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<a id="Tagawa2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tagawa, A., Tan, C.-F., Kikugawa, K., Fukase, M., Nakano, R., Onodera, O., Nishizawa, M., Takahashi, H.
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<strong>Familial amyotrophic lateral sclerosis: a SOD1-unrelated Japanese family of bulbar type with Bunina bodies and ubiquitin-positive skein-like inclusions in lower motor neurons.</strong>
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[<a href="https://doi.org/10.1007/s00401-006-0151-z" target="_blank">Full Text</a>]
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<div class="">
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<p class="mim-text-font">
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Taylor, L. M., McMillan, P. J., Liachko, N. F., Strovas, T. J., Ghetti, B., Bird, T. D., Keene, C. D., Kraemer, B. C.
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[<a href="https://doi.org/10.1186/s13024-018-0237-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1084/jem.20092164" target="_blank">Full Text</a>]
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<div class="">
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18396105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18396105</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18396105[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=18396105" 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/S1474-4422(08)70071-1" target="_blank">Full Text</a>]
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Vogler, T. O., Wheeler, J. R., Nguyen, E. D., Hughes, M. P., Britson, K. A., Lester, E., Rao, B., Dalla Betta, N., Whitney, O. N., Ewachiw, T. E., Gomes, E., Shorter, J., Lloyd, T. E., Eisenberg, D. S., Taylor, J. P., Johnson, A. M., Olwin, B. B., Parker, R.
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[<a href="https://doi.org/10.1038/s41586-018-0665-2" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14667816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14667816</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14667816" 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/s0888-7543(03)00214-3" target="_blank">Full Text</a>]
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<a id="41" class="mim-anchor"></a>
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<a id="Watanabe2013" class="mim-anchor"></a>
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<p class="mim-text-font">
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Watanabe, S., Kaneko, K., Yamanaka, K.
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<strong>Accelerated disease onset with stabilized familial amyotrophic lateral sclerosis (ALS)-linked mutant TDP-43 proteins.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23235148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23235148</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23235148[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=23235148" 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.M112.433615" target="_blank">Full Text</a>]
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<a id="42" class="mim-anchor"></a>
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<a id="Wegorzewska2009" class="mim-anchor"></a>
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<div class="">
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Wegorzewska, I., Bell, S., Cairns, N. J., Miller, T. M., Baloh, R. H.
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<strong>TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19833869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19833869</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19833869[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=19833869" 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/10.1073/pnas.0908767106" target="_blank">Full Text</a>]
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<a id="Wils2010" class="mim-anchor"></a>
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Wils, H., Kleinberger, G., Janssens, J., Pereson, S., Joris, G., Cuijt, I., Smits, V., Ceuterick-de Groote, C., Van Broeckhoven, C., Kumar-Singh, S.
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[<a href="https://doi.org/10.1073/pnas.0912417107" target="_blank">Full Text</a>]
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<a id="Woerner2016" class="mim-anchor"></a>
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Woerner, A. C., Frottin, F., Hornburg, D., Feng, L. R., Meissner, F., Patra, M., Tatzelt, J., Mann, M., Winklhofer, K. F., Hartl, F. U., Hipp, M. S.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26634439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26634439</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26634439" 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.aad2033" target="_blank">Full Text</a>]
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<a id="Xia2016" class="mim-anchor"></a>
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Xia, Q., Wang, G., Wang, H., Hu, Q., Ying, Z.
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<strong>Folliculin, a tumor suppressor associated with Birt-Hogg-Dube (BHD) syndrome, is a novel modifier of TDP-43 cytoplasmic translocation and aggregation.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26516189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26516189</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26516189" 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/ddv450" target="_blank">Full Text</a>]
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<a id="Yokoseki2008" class="mim-anchor"></a>
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Yokoseki, A., Shiga, A., Tan, C.-F., Tagawa, A., Kaneko, H., Koyama, A., Eguchi, H., Tsujino, A., Ikeuchi, T., Kakita, A., Okamoto, K., Nishizawa, M., Takahashi, H., Onodera, O.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18438952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18438952</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18438952" 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.21392" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Bao Lige - updated : 06/05/2024
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Ada Hamosh - updated : 11/28/2022<br>Bao Lige - updated : 06/30/2021<br>Ada Hamosh - updated : 02/22/2019<br>Ada Hamosh - updated : 03/12/2018<br>Ada Hamosh - updated : 09/14/2016<br>Patricia A. Hartz - updated : 06/07/2016<br>Patricia A. Hartz - updated : 2/16/2016<br>Cassandra L. Kniffin - updated : 10/27/2015<br>Patricia A. Hartz - updated : 4/8/2014<br>Cassandra L. Kniffin - updated : 3/6/2014<br>George E. Tiller - updated : 8/28/2013<br>Cassandra L. Kniffin - updated : 8/6/2013<br>Cassandra L. Kniffin - updated : 3/7/2013<br>Cassandra L. Kniffin - updated : 2/14/2013<br>Ada Hamosh - updated : 2/1/2013<br>Patricia A. Hartz - updated : 9/20/2012<br>Cassandra L. Kniffin - updated : 4/23/2012<br>Cassandra L. Kniffin - updated : 10/5/2011<br>George E. Tiller - updated : 2/8/2011<br>Paul J. Converse - updated : 2/7/2011<br>Cassandra L. Kniffin - updated : 1/14/2011<br>Cassandra L. Kniffin - updated : 9/28/2010<br>Ada Hamosh - updated : 9/14/2010<br>Cassandra L. Kniffin - updated : 10/27/2009<br>Cassandra L. Kniffin - updated : 7/14/2009<br>Cassandra L. Kniffin - updated : 3/27/2009<br>Cassandra L. Kniffin - updated : 3/18/2009<br>Carol A. Bocchini - updated : 11/7/2008<br>Cassandra L. Kniffin - updated : 10/8/2008<br>Victor A. McKusick - updated : 5/29/2008<br>Cassandra L. Kniffin - updated : 5/22/2008<br>Ada Hamosh - updated : 5/8/2008<br>Cassandra L. Kniffin - updated : 1/2/2008<br>Ada Hamosh - updated : 10/25/2006<br>Victor A. McKusick - updated : 5/28/2004<br>Patricia A. Hartz - updated : 2/6/2004
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Creation Date:
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Paul J. Converse : 6/26/2000
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mgross : 06/05/2024
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mgross : 06/05/2024<br>carol : 11/29/2022<br>alopez : 11/28/2022<br>alopez : 11/28/2022<br>mgross : 06/30/2021<br>alopez : 02/22/2019<br>alopez : 03/12/2018<br>carol : 04/27/2017<br>alopez : 09/14/2016<br>mgross : 06/07/2016<br>mgross : 2/16/2016<br>carol : 10/28/2015<br>ckniffin : 10/27/2015<br>carol : 2/4/2015<br>mgross : 4/17/2014<br>mcolton : 4/8/2014<br>alopez : 3/25/2014<br>mcolton : 3/7/2014<br>ckniffin : 3/6/2014<br>carol : 9/16/2013<br>carol : 9/11/2013<br>tpirozzi : 8/30/2013<br>tpirozzi : 8/28/2013<br>tpirozzi : 8/28/2013<br>carol : 8/9/2013<br>ckniffin : 8/6/2013<br>alopez : 3/13/2013<br>ckniffin : 3/7/2013<br>alopez : 2/20/2013<br>ckniffin : 2/14/2013<br>alopez : 2/7/2013<br>terry : 2/1/2013<br>mgross : 9/26/2012<br>terry : 9/20/2012<br>terry : 9/14/2012<br>terry : 7/27/2012<br>carol : 4/26/2012<br>ckniffin : 4/23/2012<br>carol : 10/13/2011<br>ckniffin : 10/5/2011<br>wwang : 5/18/2011<br>terry : 3/16/2011<br>wwang : 3/14/2011<br>terry : 2/8/2011<br>mgross : 2/8/2011<br>terry : 2/7/2011<br>wwang : 2/7/2011<br>ckniffin : 1/14/2011<br>ckniffin : 10/6/2010<br>wwang : 9/29/2010<br>ckniffin : 9/28/2010<br>alopez : 9/21/2010<br>alopez : 9/21/2010<br>terry : 9/14/2010<br>wwang : 11/16/2009<br>ckniffin : 10/27/2009<br>wwang : 7/31/2009<br>ckniffin : 7/14/2009<br>wwang : 3/31/2009<br>ckniffin : 3/27/2009<br>wwang : 3/26/2009<br>ckniffin : 3/18/2009<br>carol : 11/7/2008<br>wwang : 10/15/2008<br>ckniffin : 10/8/2008<br>alopez : 5/29/2008<br>alopez : 5/29/2008<br>ckniffin : 5/22/2008<br>alopez : 5/21/2008<br>terry : 5/8/2008<br>wwang : 1/22/2008<br>ckniffin : 1/2/2008<br>alopez : 11/2/2006<br>terry : 10/25/2006<br>alopez : 5/28/2004<br>mgross : 2/6/2004<br>mgross : 6/27/2000<br>mgross : 6/26/2000
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<strong>*</strong> 605078
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TAR DNA-BINDING PROTEIN; TARDBP
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TAR DNA-BINDING PROTEIN, 43-KD; TDP43
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<strong><em>HGNC Approved Gene Symbol: TARDBP</em></strong>
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Cytogenetic location: 1p36.22
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Inheritance
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1p36.22
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Amyotrophic lateral sclerosis 10, with or without FTD
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<span class="mim-font">
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612069
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Autosomal dominant
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3
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Frontotemporal lobar degeneration, TARDBP-related
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612069
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Autosomal dominant
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>TARDBP is a predominantly nuclear RNA/DNA-binding protein that functions in RNA processing and metabolism, including RNA transcription, splicing, transport, and stability. Following cell stress, TARDBP also localizes to cytoplasmic stress granules and may play a role in stress granule formation (summary by Xia et al., 2016). </p>
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<strong>Cloning and Expression</strong>
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<p>Human immunodeficiency virus (HIV)-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNA genome that produces a chromosomally integrated DNA during the replicative cycle. The HIV Tat protein (see 601409), a transcription-activating protein that binds to the bulge region of a stable stem-bulge-loop structure, TAR RNA, activates the HIV-1 long terminal repeat (LTR). Tat activates the LTR less efficiently in rodent than in human cells, suggesting that cellular RNA-binding proteins are also involved in the regulation of HIV replication. TAR DNA may possess distinct regulatory elements that play a role in modulating HIV-1 gene expression. To characterize cellular factors that bind to TAR DNA, Ou et al. (1995) screened a HeLa cell cDNA library using a TAR DNA probe and identified a cDNA encoding a 43-kD TAR DNA-binding protein, TARDBP, which they called TDP43. The deduced 414-amino acid TARDBP contains a ribonucleoprotein (RNP)-binding domain and a glycine-rich region. Northern blot analysis detected a ubiquitously expressed, 2.8-kb TARDBP transcript. SDS-PAGE analysis showed that recombinant and native TARDBP are expressed as 43-kD proteins. </p><p>By database analysis and cDNA cloning, Wang et al. (2004) determined that the TARDBP gene generates at least 11 mRNA species by alternative splicing. The shorter transcripts encode proteins lacking the glycine-rich domain, which is required for the exon-skipping activity of TARDBP. </p><p>Benajiba et al. (2009) stated that TDP43 contains 2 RNA recognition motifs, a nuclear export domain, and a C-terminal domain that is essential for binding to heterogeneous nuclear ribonucleoproteins (hnRNPs) and for splicing inhibition. TDP43 is normally localized in the nucleus, but in pathologic conditions, the cleaved form of TDP43 is mainly present in the cytoplasm. </p>
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<strong>Gene Structure</strong>
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</div>
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<span class="mim-text-font">
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<p>Wang et al. (2004) determined that the TARDBP gene contains 6 exons. </p>
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<strong>Mapping</strong>
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<p>By genomic sequence analysis, Wang et al. (2004) mapped the TARDBP gene to chromosome 1p36.21. They also identified intronless TARDBP-like pseudogenes on chromosomes 2, 6, 8, 13, and 20 that likely originated from retrotransposition events. Wang et al. (2004) mapped the mouse Tardbp gene to chromosome 4E2 in a region that shows homology of synteny to human chromosome 1p36. </p>
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<strong>Gene Function</strong>
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<p>Functional analysis by Ou et al. (1995) indicated that TARDBP does not bind RNA. Gel retardation analysis followed by Western blot analysis (Shift-Western analysis) demonstrated that the RNP-binding motifs of TARDBP bind to the pyrimidine-rich motifs of TAR DNA. In an in vitro transcription analysis, increasing amounts of TARDBP, in the presence or absence of Tat, decreased the level of transcription from the HIV-1 LTR but not from the adenovirus major late promoter. </p><p>Using reporter plasmids, Wang et al. (2004) determined that deletion of the glycine-rich domain of mouse Tardbp resulted in loss of about 90% of its ability to activate exon skipping in the CFTR gene (602421). </p><p>RNA splicing mutations in the CFTR gene are thought to lead to dysfunction of several organs such as lung, sweat glands, genital tract, intestine and pancreas, producing the complex symptoms of cystic fibrosis (219700). Buratti et al. (2001) showed that TDP43 promotes skipping of exon 9 of the CFTR gene by binding specifically to the UG repeat sequence in intron 8 of the CFTR pre-mRNA. Buratti and Baralle (2001) reported the characterization and functional implications of the RNA binding properties of TDP43. Wang et al. (2004) found that the mouse homolog of human TDP43 also inhibits human CFTR exon 9 splicing in a minigene system. Buratti et al. (2004) described experiments consistent with the model in which the TG repeats in the CFTR intron 8 bind to TDP43, and this protein, in turn, inhibits splicing of exon 9. They suggested that their results provide a mechanistic explanation for the association data of Groman et al. (2004) and also an explanation for the variable phenotypic penetrance of the TG repeats. Individual and tissue-specific variability in the concentration of this inhibitory splicing factor may even determine whether an individual will develop multisystemic (non-classic CF) or monosymptomatic (CBAVD) disease. </p><p>Neumann et al. (2006) found that a hyperphosphorylated, ubiquitinated, and cleaved form of TDP43, known as pathologic TDP43, is the major disease protein in ubiquitin-positive, tau-, and alpha-synuclein-negative frontotemporal dementia (FTLD-U; 607485) and in ALS (see 105400). The signature of pathologic TDP43 in FTLD-U includes the presence of C-terminal breakdown and/or cleavage products migrating at approximately 25 kD, a 45 kD variant, and a high molecular weight TDP43-immunoreactive smear. TDP43 is normally localized primarily to the nucleus, but Neumann et al. (2006) suggested that, under pathologic conditions in FTLD-U, TDP43 is eliminated from nuclei of ubiquitinated inclusion-bearing neurons, a consequence of which may be a loss of TDP43 nuclear functions. Arai et al. (2006) also identified TDP43 as a component of ubiquitin-positive tau-negative neuronal and glial inclusions in frontotemporal lobar degeneration and ALS. Biochemical analysis suggested that abnormal phosphorylation of TDP43 may be involved in the pathogenesis of these disorders. The findings were similar to those reported by Neumann et al. (2006). </p><p>Mackenzie et al. (2007) identified TDP43-immunoreactive neuronal and glial cytoplasmic inclusions in 59 cases of sporadic ALS, 26 cases of ALS with dementia, and 11 cases of SOD1 (147450)-negative familial ALS. Immunofluorescence confirmed colocalization of TDP43 and ubiquitin within the inclusions. In contrast, TDP43 was not detected in any of 15 patients with SOD1-positive ALS. The authors suggested that these findings represented differing pathogenic mechanisms. </p><p>Elden et al. (2010) showed that ataxin-2 (601517), a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2 (183090), is a potent modifier of TDP43 toxicity in animal and cellular models of ALS. ATXN2 and TDP43 associate in a complex that depends on RNA. In spinal cord neurons of ALS patients, ATXN2 is abnormally localized; likewise, TDP43 shows mislocalization in spinocerebellar ataxia-2. To assess the involvement of ATXN2 in ALS, Elden et al. (2010) analyzed the length of the polyQ repeat in the ATXN2 gene in 915 ALS patients and 980 controls. The authors found that intermediate-length polyQ expansions (27 to 33 glutamines) in ATXN2 were significantly associated with ALS (4.7% of cases; 1.4% of controls). </p><p>Armakola et al. (2012) reported results from 2 genomewide loss-of-function TDP43 toxicity suppressor screens in yeast. The strongest suppressor of TDP43 toxicity was deletion of DBR1 (607024), which encodes an RNA lariat debranching enzyme. Armakola et al. (2012) showed that, in the absence of DBR1 enzymatic activity, intronic lariats accumulate in the cytoplasm and likely act as decoys to sequester TDP43, preventing it from interfering with essential cellular RNAs and RNA-binding proteins. Knockdown of DBR1 in a human neuronal cell line or in primary rat neurons was also sufficient to rescue TDP43 toxicity. Armakola et al. (2012) concluded that their findings provided insight into TDP43-mediated cytotoxicity and suggested that decreasing DBR1 activity could be a potential therapeutic approach for ALS. </p><p>Ling et al. (2015) found that depletion of Tardbp in mouse embryonic stem cells resulted in the splicing of cryptic exons into mRNA, often disrupting their translation and promoting nonsense-mediated mRNA decay. Similar results were observed in human HeLa cells. Enforced repression of cryptic exons prevented cell death in Tardbp-deficient cells. The findings suggested that TARDBP normally acts to repress the splicing of nonconserved cryptic exons, thereby maintaining intron integrity. Postmortem brain tissue from patients with ALS/FTD showed that repression of cryptic exons was impaired, suggesting that this splicing defect could contribute to TARDBP-proteinopathy in certain neurodegenerative diseases. </p><p>By immunoprecipitation analysis of transfected HEK293 cells, followed by protein pull-down assays, Xia et al. (2016) showed that folliculin (FLCN; 607273) interacted directly with TDP43. Overexpression of FLCN led to localization of TDP43 in cytoplasm, where it colocalized with markers of lysosomes, autophagosomes, and the ubiquitin-proteasome system. Under arsenite stress, TDP43 colocalized with stress granules. In contrast, RNA interference-mediated depletion of FLCN in arsenite-treated cells caused dissociation of TDP43 from stress granules and nuclear accumulation of TDP43. Xia et al. (2016) concluded that FLCN is critical for TDP43 translocation from nucleus to cytoplasm, which is required for stress granule assembly. </p><p>Woerner et al. (2016) analyzed the compartment specificity of aggregate toxicity using artificial beta-sheet proteins, as well as fragments of mutant huntingtin (613004) and TDP43. Aggregation in the cytoplasm interfered with nucleocytoplasmic protein and RNA transport. In contrast, the same proteins did not inhibit transport when forming inclusions in the nucleus at or around the nucleolus. Protein aggregation in the cytoplasm, but not the nucleus, caused the sequestration and mislocalization of proteins containing disordered and low-complexity sequences, including multiple factors of the nuclear import and export machinery. Thus, Woerner et al. (2016) concluded that impairment of nucleocytoplasmic transport may contribute to the cellular pathology of various aggregate deposition diseases. </p><p>A decrease in ataxin-2 (601517) suppresses TDP43 toxicity in yeast and flies, and intermediate-length polyglutamine expansions in the ataxin-2 gene increase the risk of ALS (see 183090). Becker et al. (2017) used 2 independent approaches to test whether decreasing ataxin-2 levels could mitigate disease in a mouse model of TDP43 proteinopathy. First, they crossed ataxin-2 knockout mice with TDP43 transgenic mice. The decrease in ataxin-2 reduced aggregation of TDP43, markedly increased survival, and improved motor function. Second, in a more therapeutically applicable approach, Becker et al. (2017) administered antisense oligonucleotides targeting ataxin-2 to the central nervous system of TDP43 transgenic mice. This single treatment markedly extended survival. Becker et al. (2017) suggested that because TDP43 aggregation is a component of nearly all cases of ALS, targeting ataxin-2 could represent a broadly effective therapeutic strategy. </p><p>Vogler et al. (2018) demonstrated that TDP43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which the authors termed myogranules, during regeneration of skeletal muscle in mice and humans. Myogranules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibers mature. Although myogranules occur during normal skeletal muscle regeneration, myogranules can seed TDP43 amyloid fibrils in vitro and were increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myogranules could be the source of cytoplasmic TDP43 aggregates that commonly occur in neuromuscular diseases such as ALS and inclusion body myopathy. </p><p>Taylor et al. (2018) showed that patients with FTLD with tau inclusions (see 600274) or TDP43 inclusions had elevated expression of both TTBK1 (619415) and TTBK2 (611695) in cortical and hippocampal neurons and that TTBK1 and TTBK2 colocalized with phosphorylated proteins. </p><p>Shao et al. (2022) studied the interplay of the FTD-ALS-associated genes C9ORF72 (614260), TBK1 (604834), and TDP43. Shao et al. (2022) found that TBK1 is phosphorylated in response to C9ORF72 poly(gly-ala; GA) aggregation and sequestered into inclusions, resulting in decreased TBK1 activity and contributing to neurodegeneration. Reducing TBK1 activity in mice using a knockin mutation exacerbated poly(GA)-induced phenotypes, including increased TDP43 pathology and the accumulation of defective endosomes in poly(GA)-positive neurons. The authors postulated a disruption of the endosomal-lysosomal pathway in FTD-ALS, leading to increased susceptibility to protein aggregation, driving TDP43 proteinopathy and neurodegeneration. </p><p>Hruska-Plochan et al. (2024) generated human neural stem cells from induced pluripotent stem cells derived from normal human skin fibroblasts and found that they were self-renewing and could form functional networks, which the authors called iNets, with neuronal and glial maturation similar to that of cortical organoids. Overexpression of wildtype TDP43 in a minority of neurons within iNets led to progressive fragmentation and aggregation of TDP43, resulting in partial loss of function and neurotoxicity. Single-cell transcriptomic analysis revealed a novel set of misregulated RNA targets in TDP43-overexpressing neurons and in patients with TDP43 proteinopathies exhibiting loss of nuclear TDP43. The strongest misregulated target was NPTX2 (600750), whose levels were controlled by TDP43 binding to its 3-prime UTR. NPTX2 exhibited neurotoxicity when overexpressed in iNets, whereas correcting NPTX2 misregulation partially rescued neurons from TDP43-induced neurodegeneration. NPTX2 was consistently misaccumulated in neurons from patients with ALS and frontotemporal lobar degeneration with TDP43 pathology. The results directly linked TDP43 misregulation and NPTX2 accumulation, thereby revealing a TDP43-dependent pathway of neurotoxicity. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p>Lattante et al. (2013) provided a review of TARDBP mutations associated with ALS10 (612069). TARDPB mutations occur in about 3% of patients with familial ALS and in 1.5% of patients with sporadic disease. </p><p>Gitcho et al. (2009) noted that TDP43 was first identified as the major pathologic protein of ubiquitin-positive, tau-negative inclusions of frontotemporal lobar degeneration (FTLDU; 607485), FTLD with motor neuron disease (FTDMND; 105500), and ALS/MND (ALS10). These disorders are now considered to represent different clinical manifestations of the same underlying molecular pathology, namely TDP43 proteinopathy. The differing clinical phenotypes of these overlapping disorders most likely reflect the selective vulnerability of different segments of the neuraxis to neurodegeneration. </p><p>In a family segregating autosomal dominant ALS and 2 sporadic cases (see ALS10, 612069), Sreedharan et al. (2008) identified mutations in the TARDBP gene. All 3 mutations, M337V (605078.0001), Q331K (605078.0002), and G294A (605078.0001) occurred in a highly conserved region of the C terminus of TDP43 involved in protein-protein interactions. To assess the functional significance of these mutations, Sreedharan et al. (2008) expressed tagged TDP43(wildtype), TDP43(Q331K), and TDP43(M337V) in Chinese hamster ovary (CHO) cells. Immunofluorescent staining of cells 48 hours after transfection showed abundant expression of transfected TDP43, with no obvious differences in subcellular distribution or aggregation between mutant and wildtype proteins. Expression of these tagged proteins in spinal cord of stage 14 chick embryos demonstrated dramatic reduction in maturation in embryos expressing mutant versus wildtype TDP43, with a failure to develop normal limb and tail buds. While chick embryo development proceeded normally over 48 hours with TDP43(wildtype), at 24 hours only 5 to 15% of those embryos expressing mutant TDP43 had reached the normal stage of maturation. TUNEL staining demonstrated a significant increase in the number of apoptotic nuclei in embryos expressing either mutant when compared with wildtype. Sreedharan et al. (2008) concluded that their results suggested a toxic gain-of-function or dominant-negative effect of mutant TDP43. </p><p>In affected members of a Japanese family with ALS previously described by Tagawa et al. (2007), Yokoseki et al. (2008) identified a heterozygous mutation in the TARDBP gene (Q343R; 605078.0008). </p><p>In affected members of a European family with ALS10, Gitcho et al. (2008) identified a heterozygous mutation in the TARDBP gene (A315T; 605078.0009). </p><p>Van Deerlin et al. (2008) identified heterozygous mutations in the TARDBP gene (605078.0004; 605078.0005) in affected individuals of 2 unrelated families with autosomal dominant ALS10. </p><p>Kabashi et al. (2008) screened a panel of familial and sporadic ALS cases for TARDBP mutations. They found 8 missense mutations in 9 individuals, 6 from individuals with sporadic ALS and 3 from those with familial ALS, and a concurring increase of a smaller TDP43 product. </p><p>By sequence analysis, Kabashi et al. (2009) did not find any pathogenic mutations in the TARDBP gene among 125 French Canadian patients with dopa-responsive Parkinson disease (PD; 168600). </p><p>Kuhnlein et al. (2008) identified mutations in the TARDBP gene in 2 (6.5%) of 31 probands with non-SOD1 familial ALS. </p><p>Kovacs et al. (2009) identified a heterozygous mutation in the TARDBP gene (K263E; 605078.0011) in a Hungarian man with frontotemporal lobar degeneration beginning at age 35 years. He had a rapidly progressive course, resulting in death at age 37., Neurologic examination showed supranuclear gaze palsy, hyperkinetic choreiform movements, motor stereotypies, and primitive reflexes. Motor neuron disease signs, rigidity, and cerebellar ataxia were not present. Phospho-TDP43-immunoreactive deposits were present in neuronal cytoplasmic inclusions in various brain regions, including the cortex, </p><p>Gitcho et al. (2009) identified a heterozygous 2076G-A transition in the 3-prime untranslated region of the TARDBP gene (605078.0012) in affected members of 2 unrelated families with either ALS10 with or without frontotemporal dementia or FTLD (see 612069). The first family had 2 mutation carriers with a variable phenotype: the proband was a woman with frontotemporal dementia without motor disease, whereas her brother had lower motor neuron disease without dementia. The father and mother, from whom DNA was not available, had ALS and lower motor neuron disease, respectively, and it was not clear which parent likely transmitted the TARDBP mutation. Neuropathologic analysis of the proband, who did not have motor neuron disease, showed cortical atrophy, neuronal loss in the hippocampus, hippocampal sclerosis, and TDP43-positive neuronal cytoplasmic inclusions in the cortex and hippocampus. The brother's neuropathologic findings were consistent with ALS and showed TDP43-immunoreactivity in the anterior horn cells of the spinal cord and neuronal cytoplasmic inclusions in the hippocampus. The second family included a patient with familial ALS; no neuropathology was available for that patient. </p><p>Millecamps et al. (2010) identified 6 different missense mutations in the TARDBP gene in 7 (4.3%) of 162 French probands with familial ALS. Three of the families had been previously reported. Patients with TARDBP mutations had disease onset predominantly in the upper limb. One-third of patients had rapid disease progression, two-thirds had a medium disease course, and 1 had a slow disease course. There was evidence of incomplete penetrance. One TARDBP mutation carrier developed frontotemporal dementia 1 year after the onset of motor weakness. </p><p>Kabashi et al. (2010) tested the effects of 3 reported TARDBP mutations, A315T, (605078.0009), G348C (605078.0007), and A382T (605078.0013), in cell lines, primary cultured motor neurons, and living zebrafish embryos. Each of the 3 mutants and wildtype human TDP43 localized to nuclei when expressed in COS-1 and Neuro2A cells by transient transfection. However, when expressed in motor neurons from dissociated spinal cord cultures, these mutant TARDBP alleles were neurotoxic, concomitant with perinuclear localization and aggregation of TDP43. Overexpression of mutant human TARDBP caused a motor phenotype in zebrafish embryos consisting of shorter motor neuronal axons, premature and excessive branching, as well as swimming deficits. Knockdown of zebrafish Tardbp led to a similar phenotype, which was rescued by coexpressing wildtype but not mutant human TARDBP. Kabashi et al. (2010) suggested that both a toxic gain of function as well as a novel loss of function may be involved in the molecular mechanism by which mutant TDP43 contributes to disease pathogenesis. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Corcia et al. (2012) identified 19 patients from 9 families with ALS10 and 9 patients with apparently sporadic ALS10. The patients were French, and all carried mutations in the TARDBP gene. The mean age at onset was 53.4 years, and the upper limb was the most common site of onset. Only 2 patients had dementia. The median disease duration was 63 months; 2 patients were alive after 8 years. These patients were pooled with 117 ALS10 patients reported in the literature. Among all those with TARDBP mutations, Caucasians tended to have upper limb onset, while Asians tended to have bulbar onset. The G298S mutation (605078.0005) was associated with the shortest survival, whereas A315T (605078.0009) and M337V (605078.0001) were associated with longest duration. </p><p>By expression of 7 pathogenic ALS-associated mutant TDP43 proteins (e.g., M337V, 605078.0001; A382T, 605078.0013; G298S, 605078.0005; G348C, 605078.0007; Q343R, 605078.0008; and A315T, 605078.0009) in a differentiated neuronal cell line, Watanabe et al. (2013) found that all had consistently longer half-lives compared to the wildtype protein. Patients carrying mutations with longer half-lives showed earlier disease onset (p = 0.00252), although there was no correlation between protein half-lives and disease duration. Proteins with mutations in the nuclear export signal had an extremely long half-life, whereas a second group of mutations generated within the nuclear localization signal were less stable than wildtype. In additional studies, most of 18 ALS-linked mutant TDP43 proteins showed lower solubility to the detergent Sarkosyl compared to wildtype. A cell model in which wildtype TDP43 was stabilized caused cytotoxicity, nuclear accumulation, insolubility, proteasomal impairment with increased numbers of misfolded C-terminal cleaved TDP43 products, and dysregulation of normal mRNA processing. The findings suggested that increased stability of either wildtype or mutant TDP43 can cause a gain of toxicity through abnormal proteostasis. </p>
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<strong>Animal Model</strong>
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</h4>
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<p>Wegorzewska et al. (2009) found that transgenic mice expressing a Tdp43 A315T mutation (605078.0009) developed progressive gait abnormalities at about 3 to 4 months of age and died at about 5 months of age. Postmortem examination showed accumulation of ubiquitinated proteins selectively in the cytoplasm of neurons in cortical layer 5, including the motor cortex. The inclusions did not stain for TDP43, but the changes were associated with neuronal loss and increased glial reaction. Examination of the spinal cord of mutant mice showed degeneration of descending motor axons and ubiquitin pathology in large neurons of the ventral horn; there was also loss of motor neurons. Mutant mice also showed Tdp43 C-terminal fragments in the brain and spinal cord prior to the onset of gait abnormalities. Wegorzewska et al. (2009) concluded that since cytoplasmic Tdp43 aggregates were not present in mutant mice, they are not required for neurodegeneration. These results indicated that the selective neuronal vulnerability in Tdp43-related neurodegeneration is related to altered DNA/RNA-binding protein function rather than to toxic aggregation. </p><p>Using translating ribosome affinity purification and microarray analysis, MacNair et al. (2016) found that several mRNAs were abnormally regulated in 10-month-old symptomatic Tdp43 A315T transgenic mice compared with wildtype controls and 5-month-old presymptomatic Tdp43 A315T mice. Those upregulated over 2-fold in older Tdp43 A315T mice included Ccl4 (182284), Tdp43, Pkib (606914), and Ddx58 (609631), and those downregulated included Prickle4 (611389), Pes1 (605819), and Mthfsd (616820). Expression of DDX58 and MTHFSD was similarly misregulated in human ALS motor neurons, and RNA immunoprecipitation analysis showed that Mthfsd and Ddx58 were direct targets of Tdp43 in transfected mouse neuroblastoma cells. </p><p>Tsai et al. (2010) generated an FTLDU mouse model by transgenically overexpressing Tdp43 in forebrain. Transgenic mice exhibited impaired learning and memory, progressive motor dysfunction, and hippocampal atrophy. The impairments were accompanied by reduced levels of phosphorylated Erk (see MAPK1; 176948) and phosphorylated Creb (CREB1; 123810) and increased levels of gliosis in the brains of transgenic mice. Cells with Tdp43-positive, ubiquitin-positive neuronal cytoplasmic inclusions (NCIs) and Tdp43-deleted nuclei appeared in transgenic mouse brains in an age-dependent manner. Tsai et al. (2010) concluded that increased levels of TDP43 protein in forebrain are sufficient to lead to formation of TDP43-positive, ubiquitin-positive NCIs and neurodegeneration. </p><p>Independently, Wils et al. (2010) observed neurodegeneration in transgenic mice overexpressing wildtype human TDP43. Homozygous and hemizygous transgenic mice showed dose-dependent degeneration of cortical and spinal motor neurons and developed spastic quadriplegia similar to ALS. Transgenic mice also developed dose-dependent degeneration of nonmotor cortical and subcortical neurons characteristic of FTLD. Affected neurons of the spinal cord and brain showed nuclear and cytoplasmic aggregates of ubiquitinated and phosphorylated TDP43. The characteristic, approximately 25-kD TDP43 C-terminal fragments were also recovered from nuclear fractions and correlated with disease development and progression in transgenic mice. </p><p>Ash et al. (2010) engineered panneuronal expression of human TDP43 in C. elegans to generate an in vivo model of TDP43 function and neurotoxicity. Transgenic worms with neuronal expression of human TDP43 exhibited an 'uncoordinated' phenotype and had abnormal motoneuron synapses. C. elegans contains a single putative ortholog of TDP43, designated tdp1, which could support alternative splicing of CFTR (602421) in a cell-based assay. Neuronal overexpression of tdp1 also resulted in an uncoordinated phenotype, whereas deletion of the tdp1 gene did not affect movement or alter motoneuron synapses. Wildtype human TDP43 expressed in C. elegans localized to the nucleus. TDP43 mutants missing either RNA recognition domain RRM1 or RRM2 completely blocked neurotoxicity, as did a mutant missing its C-terminal domain. These TDP43 mutants still accumulated in the nucleus, although their subnuclear distribution was altered. Fusion of the tdp1 C-terminal domain to a TDP43 N terminus restored normal subnuclear localization and toxicity in C. elegans and CFTR splicing in cell-based assays. Overexpression of wildtype TDP43 in differentiated M17 cells also resulted in cell toxicity. Ash et al. (2010) concluded that overexpression of wildtype TDP43 is sufficient to induce neurotoxicity. </p><p>Diaper et al. (2013) found that deletion of the TAR DNA-binding protein homolog (Tbph) in Drosophila caused impaired synaptic transmission at the larval and adult neuromuscular junction. Impaired presynaptic transmission was the earliest Tbph-related defect. Overexpression of Tbph in adults also resulted in synaptic defects and age-related progressive degeneration of neurons involved in motor control. Progressive neurodegeneration was also seen with inactivated Tbph. </p><p>Taylor et al. (2018) showed that transgenic C. elegans expressing the kinase catalytic domain of human TTBK1 or TTBK2 were behaviorally normal. However, coexpression of TTBK1, but not TTBK2, with TDP43 led to behavioral abnormalities and increased phosphorylation of TDP43. </p>
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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>13 Selected Examples):</strong>
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<h4>
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<span class="mim-font">
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<strong>.0001 AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</strong>
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TARDBP, MET337VAL
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<br />
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SNP: rs80356730,
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gnomAD: rs80356730,
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ClinVar: RCV000005539, RCV000693006, RCV001090806
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<p>In an English family segregating autosomal dominant amyotrophic lateral sclerosis without frontotemporal dementia (612069), Sreedharan et al. (2008) identified an A-to-G transition at nucleotide 1009 in exon 6 of the TARDBP gene, resulting in a methionine-to-valine substitution at codon 337 (M337V). Methionine at this position is invariant in human, orangutan, mouse, opossum, chicken, frog, and zebrafish. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>.0002 AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</strong>
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</span>
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</h4>
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<div>
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TARDBP, GLN331LYS
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<br />
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SNP: rs80356727,
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ClinVar: RCV000005540
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</span>
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<span class="mim-text-font">
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<p>In a 72-year-old Caucasian British man who developed limb-onset ALS (612069) with a disease duration of 3 years, Sreedharan et al. (2008) identified a C-to-A transversion at nucleotide 991 in exon 6 of the TARDBP gene, resulting in a glutamine-to-lysine substitution at codon 331 (Q331K). </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>.0003 AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</strong>
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</span>
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</h4>
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<div>
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TARDBP, GLY294ALA
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<br />
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SNP: rs80356721,
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gnomAD: rs80356721,
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ClinVar: RCV000005541, RCV002371764
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<span class="mim-text-font">
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<p>In an Australian man who developed limb-onset ALS (612069) at age 65 with a disease duration of 5 years and no atypical features, Sreedharan et al. (2008) identified a G-to-C transversion at nucleotide 881 in exon 6 of the TARDBP gene, resulting in a glycine-to-alanine substitution at codon 294 (G294A). </p><p>Luquin et al. (2009) identified the G294A mutation in postmortem brain tissue from a patient with sporadic ALS. No clinical information was given. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>.0004 AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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TARDBP, GLY290ALA
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<br />
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SNP: rs121908395,
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ClinVar: RCV000005542, RCV001054737
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</span>
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<span class="mim-text-font">
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<p>In a Caucasian father and daughter with autosomal dominant ALS10 (612069), Van Deerlin et al. (2008) identified a heterozygous 869G-C transversion in exon 6 of the TARDBP gene, resulting in a gly290-to-ala (G290A) substitution in the C-terminal region of TDP43. The mutation was not identified in 747 white controls. The daughter presented with dysarthria and dysphagia at age 51 years and had a rapidly progressive course involving the limbs and respiration. She died after 13 months. Her father had presented with arm weakness at age 47 years and died after 16 months. Postmortem examination showed findings consistent with ALS. </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>.0005 AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</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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TARDBP, GLY298SER
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<br />
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SNP: rs4884357,
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gnomAD: rs4884357,
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ClinVar: RCV000005543, RCV000713825, RCV001851670, RCV004754243
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</span>
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</div>
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<span class="mim-text-font">
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<p>In affected members of a Chinese family with autosomal dominant ALS10 (612069), Van Deerlin et al. (2008) identified a heterozygous 892G-A transition in exon 6 of the TARDBP gene, resulting in a gly298-to-ser (G298S) substitution in the C-terminal region of TDP43. The mutation was not identified in 747 white controls or 380 Chinese controls. Five patients in 2 generations were affected with onset between ages 41 and 60 years. Most showed rapid progression with death within 1 or 2 years. Postmortem examination of 2 patients showed changes consistent with ALS as well as TDP43-positive inclusions in upper and lower motor neurons and in various brain regions. </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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<h4>
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<span class="mim-font">
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<strong>.0006 AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</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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TARDBP, ASP169GLY
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<br />
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SNP: rs80356717,
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ClinVar: RCV000005544
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 56-year-old female with amyotrophic lateral sclerosis (612069), Kabashi et al. (2008) found a heterozygous A-to-G transition in exon 4 of the TARDBP gene (640A-G) that resulted in an asp169-to-gly substitution (D169G) in TDP43. The mutation occurred in the first RNA recognition motif (RRM1) and was predicted to abrogate RNA binding. </p>
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</span>
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<div>
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</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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TARDBP, GLY348CYS
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<br />
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SNP: rs80356733,
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ClinVar: RCV000005545, RCV000516886, RCV001851671
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 30-year-old female patient with amyotrophic lateral sclerosis (612069), Kabashi et al. (2008) detected a heterozygous G-to-T transversion at nucleotide 1176 in exon 6 of the TARDBP gene that resulted in substitution of cys for gly at codon 348 of TDP43 (G348C). The mutation, which introduced a cysteine to the C-terminal hnRNP interaction region, was predicted to increase the propensity for aggregation through the formation of intermolecular disulfide bridges. </p><p>Kuhnlein et al. (2008) identified the G348C mutation in affected members of a German family with ALS10. The proband presented at age 55 years with paresis of the right hand, which progressed rapidly to involve the arms and lower limbs and left her wheelchair-bound within 2.5 years. She died of respiratory insufficiency 3 years after disease onset. The patient's mother had died of respiratory insufficiency due to a similar disorder. There were no clinically relevant bulbar symptoms and no cognitive impairment. </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>.0008 AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</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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TARDBP, GLN343ARG
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<br />
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SNP: rs80356731,
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ClinVar: RCV000005546
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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 Japanese family with amyotrophic lateral sclerosis (612069), Yokoseki et al. (2008) identified heterozygosity for a 1028A-G transition in the TARDBP gene, resulting in a gln343-to-arg (Q343R) substitution. The mutation occurs in a highly conserved residue and was not present in 534 chromosomes in Japanese control subjects. </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>.0009 AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</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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TARDBP, ALA315THR
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<br />
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SNP: rs80356726,
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gnomAD: rs80356726,
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ClinVar: RCV000005547, RCV001384596, RCV004546411
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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 European family with amyotrophic lateral sclerosis (612069), Gitcho et al. (2008) identified heterozygosity for a 1077G-A transition in exon 6 of the TARDBP gene, resulting in an ala315-to-thr substitution. The mutation occurs in a highly conserved residue and was not found in 1,505 ethnically matched elderly control subjects. </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>.0010 AMYOTROPHIC LATERAL SCLEROSIS 10 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</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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TARDBP, GLY295SER
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<br />
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SNP: rs80356723,
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gnomAD: rs80356723,
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ClinVar: RCV000020674, RCV003764615
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a woman with ALS10 (612069), Benajiba et al. (2009) identified a heterozygous 883G-A transition in exon 6 of the TARDBP gene, resulting in a gly295-to-ser (G295S) substitution in the hnRNP-binding domain. She also developed semantic frontotemporal dementia. Her sister, who carried the mutation, and their deceased father, who presumably carried the mutation, both had motor neuron disease without dementia. The G295S mutation was also identified in an unrelated woman with the behavioral variant of frontotemporal dementia and motor neuron disease. The mutation was not found in 400 control individuals. </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>.0011 FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, TARDBP-RELATED</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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TARDBP, LYS263GLU
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<br />
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SNP: rs267607102,
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ClinVar: RCV000005549
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a Hungarian man with frontotemporal lobar degeneration (see 612069), Kovacs et al. (2009) identified a heterozygous A-to-G transition in exon 6 of the TARDBP gene, resulting in a lys263-to-glu (K263E) substitution in the highly conserved C terminus. The mutation was not found in 530 controls. The patient developed personality changes beginning at age 35 years. This was followed by a rapid deterioration in attention and thinking, with psychomotor agitation and insomnia, consistent with FTD. Neurologic examination showed supranuclear gaze palsy, hyperkinetic choreiform movements, motor stereotypies, and primitive reflexes. Motor neuron disease signs, rigidity, and cerebellar ataxia were not present. He died at age 37 years of pulmonary edema secondary to cardiac failure. Neuropathologic examination neuronal loss and astrogliosis in the subcortical gray matter. Phospho-TDP43-immunoreactive deposits were present in neuronal cytoplasmic inclusions in various brain regions, including the cortex, basal ganglia, thalamus, and brainstem. The findings indicated that TARDBP mutations can be associated with a wider clinicopathologic spectrum of disorders than originally thought. </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>.0012 AMYOTROPHIC LATERAL SCLEROSIS 10 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</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">
|
|
FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, TARDBP-RELATED, INCLUDED
|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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TARDBP, 2076G-A, 3-PRIME UTR
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<br />
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SNP: rs387906334,
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ClinVar: RCV000005550, RCV000005551, RCV002512811
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In affected members of 2 unrelated families with either ALS10 with or without frontotemporal dementia (612069) or FTLD (see 612069), Gitcho et al. (2009) identified a heterozygous 2076G-A transition in the 3-prime untranslated region of the TARDBP gene adjacent to the last exon, exon 6. The first family had 2 mutation carriers with a variable phenotype: the proband was a woman with frontotemporal dementia without motor disease, whereas her brother had lower motor neuron disease without dementia. The father and mother, from whom DNA was not available, had ALS and lower motor neuron disease, respectively, and it was not clear which parent likely transmitted the TARDBP mutation. Neuropathologic analysis of the proband, who did not have motor neuron disease, showed cortical atrophy, neuronal loss in the hippocampus, hippocampal sclerosis, and TDP43-positive neuronal cytoplasmic inclusions in the cortex and hippocampus. There was no evidence of motor neuron loss from the motor nuclei of the brainstem. The brother's neuropathologic findings were consistent with ALS and showed TDP43-immunoreactivity in the anterior horn cells of the spinal cord and neuronal cytoplasmic inclusions in the hippocampus. The second family included a patient with familial ALS; no neuropathology was available for that patient. The 2076G-A variant is highly conserved across species, suggesting functional importance, and was not found in 974 control individuals. Allele-specific functional analysis showed that the 2076G-A variant was associated with a 2-fold increase in TARDBP expression. These findings suggested that a common molecular pathology can result in clinically heterogeneous phenotypes. </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>.0013 AMYOTROPHIC LATERAL SCLEROSIS 10 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, TARDBP-RELATED, INCLUDED
|
|
</span>
|
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</div>
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<div>
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<span class="mim-text-font">
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TARDBP, ALA382THR
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<br />
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SNP: rs367543041,
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gnomAD: rs367543041,
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|
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ClinVar: RCV000020663, RCV000106321, RCV000413910, RCV002513146, RCV003944833
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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 />
|
|
<p><strong><em>Amyotrophic Lateral Sclerosis 10</em></strong></p><p>
|
|
In 7 Italian probands with ALS10 (612069), Corrado et al. (2009) identified a heterozygous 1144G-A transition in exon 6 of the TARDBP gene, resulting in an ala382-to-thr (A382T) substitution. The patients were identified from a larger cohort of 666 Italian ALS patients. A382T was the most common of all TARDBP mutations and was found in 6 of 18 probands. All the patients had ALS with predominantly lower motor neuron disease affecting the upper limb, with proximal spreading; none had cognitive impairment. Haplotype analysis indicated a founder effect in 5 of 7 patients with the A382T mutation. Lymphocyte studies showed accumulation of aberrant TARDBP bands, suggesting instability of the mutant protein. </p><p>Chio et al. (2010) identified a heterozygous A382T mutation in affected members of 3 unrelated Italian families with ALS10 with frontotemporal dementia (612069). The mutation was not found in over 1,200 controls. Affected individuals developed rapidly progressive muscle atrophy and weakness associated with hyperreflexia, dysarthria, dysphagia, and respiratory insufficiency between ages 25 and 78 years. Frontotemporal dementia, characterized by disinhibition, emotional lability, apathy, and executive dysfunction, developed soon after the onset of ALS. One mutation carrier did not manifest neurologic symptoms at age 65 years. </p><p>Chio et al. (2011) identified the A382T mutation in 39 (28.7%) of 135 Sardinian patients with ALS, including 15 with familial disease and 24 with apparently sporadic disease. None of 156 ethnically matched controls carried the mutation. Haplotype analysis of 5 patients with the mutation identified a 94-SNP common risk haplotype spanning 663 kb across the TARDBP locus on chromosome 1p36.22. The findings suggested a founder effect in this population. </p><p><strong><em>Frontotemporal Dementia</em></strong></p><p>
|
|
Synofzik et al. (2014) identified a heterozygous A382T mutation in a Sardinian man with behavioral variant frontotemporal dementia without motor signs (see 612069). The patient developed rapidly progressive dementia beginning at age 31, and was severely disabled with no meaningful communication or social interaction by age 37. Brain MRI showed generalized cerebral atrophy, particularly in the anterior temporal lobe and hippocampi. The patient had no evidence of ALS. His father, who was likely a carrier based on family history, did not show signs of dementia or ALS at age 63 years. Family history was positive for ALS without dementia in 2 individuals in antecedent generations; DNA was not available from these patients. The mutation was found by massively parallel sequencing of the proband and confirmed by Sanger sequencing. The findings confirmed that TARDBP mutations can cause a pure dementia phenotype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Arai, T., Hasegawa, M., Akiyama, H., Ikeda, K., Nonaka, T., Mori, H., Mann, D., Tsuchiya, K., Yoshida, M., Hashizume, Y., Oda, T.
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|
<strong>TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.</strong>
|
|
Biochem. Biophys. Res. Commun. 351: 602-611, 2006.
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[PubMed: 17084815]
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[Full Text: https://doi.org/10.1016/j.bbrc.2006.10.093]
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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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Armakola, M., Higgins, M. J., Figley, M. D., Barmada, S. J., Scarborough, E. A., Diaz, Z., Fang, X., Shorter, J., Krogan, N. J., Finkbeiner, S., Farese, R. V., Jr., Gitler, A. D.
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<strong>Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models.</strong>
|
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Nature Genet. 44: 1302-1309, 2012.
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[PubMed: 23104007]
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[Full Text: https://doi.org/10.1038/ng.2434]
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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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Ash, P. E. A., Zhang, Y.-J., Roberts, C. M., Saldi, T., Hutter, H., Buratti, E., Petrucelli, L., Link, C. D.
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<strong>Neurotoxic effects of TDP-43 overexpression in C. elegans.</strong>
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Hum. Molec. Genet. 19: 3206-3218, 2010.
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[PubMed: 20530643]
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[Full Text: https://doi.org/10.1093/hmg/ddq230]
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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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Becker, L. A., Huang, B., Bieri, G., Ma, R., Knowles, D. A., Jafar-Nejad, P., Messing, J., Kim, H. J., Soriano, A., Auburger, G., Pulst, S. M., Taylor, J. P., Rigo, F., Gitler, A. D.
|
|
<strong>Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice.</strong>
|
|
Nature 544: 367-371, 2017.
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[PubMed: 28405022]
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[Full Text: https://doi.org/10.1038/nature22038]
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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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Benajiba, L., Le Ber, I., Camuzat, A., Lacoste, M., Thomas-Anterion, C., Couratier, P., Legallic, S., Salachas, F., Hannequin, D., Decousus, M., Lacomblez, L., Guedj, E., Golfier, V., Camu, W., Dubois, B., Campion, D., Meininger, V., Brice, A., French Clinical and Genetic Research Network on Frontotemporal Lobar Degeneration/Frontotemporal Lobar Degeneration with Motoneuron Disease.
|
|
<strong>TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration.</strong>
|
|
Ann. Neurol. 65: 470-474, 2009.
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[PubMed: 19350673]
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[Full Text: https://doi.org/10.1002/ana.21612]
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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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Buratti, E., Baralle, F. E.
|
|
<strong>Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9.</strong>
|
|
J. Biol. Chem. 276: 36337-36343, 2001.
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[PubMed: 11470789]
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[Full Text: https://doi.org/10.1074/jbc.M104236200]
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<strong>Structural diversity and functional implications of the eukaryotic TDP gene family.</strong>
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Watanabe, S., Kaneko, K., Yamanaka, K.
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<strong>Accelerated disease onset with stabilized familial amyotrophic lateral sclerosis (ALS)-linked mutant TDP-43 proteins.</strong>
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Wegorzewska, I., Bell, S., Cairns, N. J., Miller, T. M., Baloh, R. H.
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<strong>TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration.</strong>
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Woerner, A. C., Frottin, F., Hornburg, D., Feng, L. R., Meissner, F., Patra, M., Tatzelt, J., Mann, M., Winklhofer, K. F., Hartl, F. U., Hipp, M. S.
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Xia, Q., Wang, G., Wang, H., Hu, Q., Ying, Z.
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<strong>Folliculin, a tumor suppressor associated with Birt-Hogg-Dube (BHD) syndrome, is a novel modifier of TDP-43 cytoplasmic translocation and aggregation.</strong>
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Yokoseki, A., Shiga, A., Tan, C.-F., Tagawa, A., Kaneko, H., Koyama, A., Eguchi, H., Tsujino, A., Ikeuchi, T., Kakita, A., Okamoto, K., Nishizawa, M., Takahashi, H., Onodera, O.
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Bao Lige - updated : 06/05/2024<br>Ada Hamosh - updated : 11/28/2022<br>Bao Lige - updated : 06/30/2021<br>Ada Hamosh - updated : 02/22/2019<br>Ada Hamosh - updated : 03/12/2018<br>Ada Hamosh - updated : 09/14/2016<br>Patricia A. Hartz - updated : 06/07/2016<br>Patricia A. Hartz - updated : 2/16/2016<br>Cassandra L. Kniffin - updated : 10/27/2015<br>Patricia A. Hartz - updated : 4/8/2014<br>Cassandra L. Kniffin - updated : 3/6/2014<br>George E. Tiller - updated : 8/28/2013<br>Cassandra L. Kniffin - updated : 8/6/2013<br>Cassandra L. Kniffin - updated : 3/7/2013<br>Cassandra L. Kniffin - updated : 2/14/2013<br>Ada Hamosh - updated : 2/1/2013<br>Patricia A. Hartz - updated : 9/20/2012<br>Cassandra L. Kniffin - updated : 4/23/2012<br>Cassandra L. Kniffin - updated : 10/5/2011<br>George E. Tiller - updated : 2/8/2011<br>Paul J. Converse - updated : 2/7/2011<br>Cassandra L. Kniffin - updated : 1/14/2011<br>Cassandra L. Kniffin - updated : 9/28/2010<br>Ada Hamosh - updated : 9/14/2010<br>Cassandra L. Kniffin - updated : 10/27/2009<br>Cassandra L. Kniffin - updated : 7/14/2009<br>Cassandra L. Kniffin - updated : 3/27/2009<br>Cassandra L. Kniffin - updated : 3/18/2009<br>Carol A. Bocchini - updated : 11/7/2008<br>Cassandra L. Kniffin - updated : 10/8/2008<br>Victor A. McKusick - updated : 5/29/2008<br>Cassandra L. Kniffin - updated : 5/22/2008<br>Ada Hamosh - updated : 5/8/2008<br>Cassandra L. Kniffin - updated : 1/2/2008<br>Ada Hamosh - updated : 10/25/2006<br>Victor A. McKusick - updated : 5/28/2004<br>Patricia A. Hartz - updated : 2/6/2004
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