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Entry
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- *614260 - CHROMOSOME 9 OPEN READING FRAME 72; C9ORF72
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- OMIM
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<p>
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<span class="h4">*614260</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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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/614260">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 role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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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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<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=ENSG00000147894;t=ENST00000380003" 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=203228" 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=614260" 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=ENSG00000147894;t=ENST00000380003" 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_001256054,NM_018325,NM_145005" 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_018325" 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=614260" 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://www.proteinatlas.org/search/C9orf72" 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/7023568,16553757,24475849,37039612,46249752,71152412,119578962,119578963,119578964,119578965,158256286,356892156,365906244" 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/Q96LT7" 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=203228" 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=ENSG00000147894;t=ENST00000380003" 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=C9orf72" 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=C9orf72" 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+203228" 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/C9orf72" 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:203228" 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/203228" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr9&hgg_gene=ENST00000380003.8&hgg_start=27546546&hgg_end=27573866&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:28337" 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/c9orf72" 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=614260[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=614260[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/ENSG00000147894" 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=C9orf72" 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=C9orf72" 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=C9orf72" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=C9orf72&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/PA134908144" 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:28337" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1920455" 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/C9orf72#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:1920455" 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/203228/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/OMIA002725/" 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=203228" 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=WBGene00017547;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-040801-47" 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:203228" 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=C9orf72&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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614260
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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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CHROMOSOME 9 OPEN READING FRAME 72; C9ORF72
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=C9orf72" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">C9orf72</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/9/117?start=-3&limit=10&highlight=117">9p21.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:27546546-27573866&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">9:27,546,546-27,573,866</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/9/117?start=-3&limit=10&highlight=117">
|
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9p21.2
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</a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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Frontotemporal dementia and/or amyotrophic lateral sclerosis 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/105550"> 105550 </a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/614260" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/614260" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
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<p />
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<strong>TEXT</strong>
|
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</span>
|
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</span>
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</h4>
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<div>
|
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<a id="cloning" class="mim-anchor"></a>
|
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
|
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</span>
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</h4>
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</div>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#11" class="mim-tip-reference" title="DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., Kouri, N., Wojtas, A., and 16 others. <strong>Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.</strong> Neuron 72: 245-256, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944778</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944778[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944778">DeJesus-Hernandez et al. (2011)</a> characterized 3 C9ORF72 transcripts. Variants 1 and 3 contain different noncoding first exons (exons 1b and 1a, respectively) fused to coding exons 2 through 11. Both variants encode the same deduced 481-amino acid protein. Variant 2 contains exon 1a fused to coding exons 2 through 5 and encodes a deduced 222-amino acid protein. Exon 1a in variant 2 uses a different 3-prime donor site than that used by exon 1a in variant 3. RT-PCR analysis with variant-specific primers detected expression of variants 1 and 3 in all tissues examined. Variant 2 was highly expressed in testis, fetal brain, cerebellum, and frontal cortex, with lower expression in kidney, lung, and hippocampus, and no expression in liver and lymphoblasts. Western blot analysis revealed C9ORF72 proteins with apparent molecular masses of 55 and 25 kD in human lymphoblasts. Immunohistochemical analysis of brain showed that C9ORF72 was largely a neuronal cytoplasmic protein. It also seemed to localize at large presynaptic terminals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21944778" 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="#28" class="mim-tip-reference" title="Renton, A. E., Majounie, E., Waite, A., Simon-Sanchez, J., Rollinson, S., Gibbs, J. R., Schymick, J. C., Laaksovirta, H., van Swieten, J. C., Myllykangas, L., Kalimo, H., Paetau, A., and 65 others. <strong>A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.</strong> Neuron 72: 257-268, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944779</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944779[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944779">Renton et al. (2011)</a> reported C9ORF72 isoforms containing 221 and 481 amino acids. Expression array analysis detected C9ORF72 expression in all brain regions examined and spinal cord, with highest expression in cerebellum. Immunohistochemical analysis showed nuclear expression of C9ORF72 in a normal human fibroblast cell line and a mouse motor neuron cell line. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21944779" 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="DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., Kouri, N., Wojtas, A., and 16 others. <strong>Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.</strong> Neuron 72: 245-256, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944778</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944778[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944778">DeJesus-Hernandez et al. (2011)</a> determined that the C9ORF72 gene contains 12 exons, including 2 alternate noncoding first exons (exons 1a and 1b). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21944778" 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="DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., Kouri, N., Wojtas, A., and 16 others. <strong>Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.</strong> Neuron 72: 245-256, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944778</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944778[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944778">DeJesus-Hernandez et al. (2011)</a> and <a href="#28" class="mim-tip-reference" title="Renton, A. E., Majounie, E., Waite, A., Simon-Sanchez, J., Rollinson, S., Gibbs, J. R., Schymick, J. C., Laaksovirta, H., van Swieten, J. C., Myllykangas, L., Kalimo, H., Paetau, A., and 65 others. <strong>A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.</strong> Neuron 72: 257-268, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944779</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944779[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944779">Renton et al. (2011)</a> reported that the C9ORF72 gene maps to chromosome 9p21. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21944779+21944778" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#32" class="mim-tip-reference" title="Su, M.-Y., Fromm, S. A., Zoncu, R., Hurley, J. H. <strong>Structure of the C9orf72 ARF GAP complex that is haploinsufficient in ALS and FTD.</strong> Nature 585: 251-255, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32848248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32848248</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32848248[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/s41586-020-2633-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32848248">Su et al. (2020)</a> determined the structure of the C9ORF72-SMCR8 (<a href="/entry/617074">617074</a>)-WDR41 (<a href="/entry/617502">617502</a>) complex by cryoelectron microscopy. C9ORF72 and SMCR8 both contain longin and DENN (differentially expressed in normal and neoplastic cells) domains, and WDR41 is a beta-propeller protein that binds to SMCR8 such that the whole structure resembles an eye-slip hook. Contacts between WDR41 and the DENN domain of SMCR8 drive the lysosomal localization of the complex in conditions of amino acid starvation. The structure suggested that C9ORF72-SMCR8 is a GTPase-activating protein (GAP), and <a href="#32" class="mim-tip-reference" title="Su, M.-Y., Fromm, S. A., Zoncu, R., Hurley, J. H. <strong>Structure of the C9orf72 ARF GAP complex that is haploinsufficient in ALS and FTD.</strong> Nature 585: 251-255, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32848248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32848248</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32848248[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/s41586-020-2633-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32848248">Su et al. (2020)</a> found that C9ORF72-SMCR8-WDR41 acts as a GAP for the ARF family of small GTPases. <a href="#32" class="mim-tip-reference" title="Su, M.-Y., Fromm, S. A., Zoncu, R., Hurley, J. H. <strong>Structure of the C9orf72 ARF GAP complex that is haploinsufficient in ALS and FTD.</strong> Nature 585: 251-255, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32848248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32848248</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32848248[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/s41586-020-2633-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32848248">Su et al. (2020)</a> concluded that their data data shed light on the function of C9ORF72 in normal physiology, and in amyotrophic lateral sclerosis and frontotemporal degeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32848248" 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="#15" class="mim-tip-reference" title="Haeusler, A. R., Donnelly, C. J., Periz, G., Simko, E. A. J., Shaw, P. G., Kim, M.-S., Maragakis, N. J., Troncoso, J. C., Pandey, A., Sattler, R., Rothstein, J. D., Wang, J. <strong>C9orf72 nucleotide repeat structures initiate molecular cascades of disease.</strong> Nature 507: 195-200, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24598541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24598541</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24598541[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/nature13124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24598541">Haeusler et al. (2014)</a> identified a molecular mechanism by which structural polymorphism of the C9ORF72 hexanucleotide repeat expansion (HRE) leads to ALS/FTD (<a href="/entry/105550">105550</a>) pathology and defects. The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA/DNA hybrids (R-loops). The structural polymorphism causes a repeat length-dependent accumulation of transcripts aborted in the HRE region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin (<a href="/entry/164035">164035</a>) preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. <a href="#15" class="mim-tip-reference" title="Haeusler, A. R., Donnelly, C. J., Periz, G., Simko, E. A. J., Shaw, P. G., Kim, M.-S., Maragakis, N. J., Troncoso, J. C., Pandey, A., Sattler, R., Rothstein, J. D., Wang, J. <strong>C9orf72 nucleotide repeat structures initiate molecular cascades of disease.</strong> Nature 507: 195-200, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24598541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24598541</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24598541[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/nature13124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24598541">Haeusler et al. (2014)</a> concluded that distinct C9ORF72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24598541" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Farg, M. A., Sundaramoorthy, V., Sultana, J. M., Yang, S., Atkinson, R. A. K., Levina, V., Halloran, M. A., Gleeson, P. A., Blair, I. P., Soo, K. Y., King, A. E., Atkin, J. D. <strong>C9ORF72, implicated in amytrophic (sic) lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking.</strong> Hum. Molec. Genet. 23: 3579-3595, 2014. Note: Erratum: Hum. Molec. Genet. 26: 4093-4094, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24549040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24549040</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24549040[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/ddu068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24549040">Farg et al. (2014)</a> provided evidence that C9ORF72 plays a role in endosomal trafficking. Immunofluorescence studies indicated that C9ORF72 was expressed within vesicles in the nucleus and cytoplasm of human and mouse neuronal cell lines. C9ORF72 colocalized with several Rab proteins implicated in autophagy and endosomal transport, including RAB1 (<a href="/entry/179508">179508</a>), RAB7 (<a href="/entry/602298">602298</a>), and RAB11A (<a href="/entry/605570">605570</a>), in neuronal cells, mouse cortical neurons, and human spinal cord. C9ORF72 also localized with the autophagocytic marker LC3 (MAP1LC3A; <a href="/entry/601242">601242</a>). Depletion of C9ORF72 using siRNA resulted in impaired endocytosis and impaired autophagy-mediated trafficking. Immunoprecipitation studies showed that C9ORF72 interacted with additional proteins involved in cellular trafficking pathways, such as ubiquilin-2 (UBQLN2; <a href="/entry/300264">300264</a>), HNRNPA1 (<a href="/entry/164017">164017</a>), and HNRNPA2B1 (<a href="/entry/600124">600124</a>). Cellular overexpression of C9ORF72 interfered with proteasomal function and induced the formation of C9ORF72 aggregates and cytoplasmic stress bodies. <a href="#12" class="mim-tip-reference" title="Farg, M. A., Sundaramoorthy, V., Sultana, J. M., Yang, S., Atkinson, R. A. K., Levina, V., Halloran, M. A., Gleeson, P. A., Blair, I. P., Soo, K. Y., King, A. E., Atkin, J. D. <strong>C9ORF72, implicated in amytrophic (sic) lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking.</strong> Hum. Molec. Genet. 23: 3579-3595, 2014. Note: Erratum: Hum. Molec. Genet. 26: 4093-4094, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24549040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24549040</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24549040[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/ddu068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24549040">Farg et al. (2014)</a> suggested that C9ORF72 functions as a Rab guanine nucleotide exchange factor (Rab GEF) that regulates intracellular trafficking. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24549040" 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>Both the sense and antisense transcripts of the GGGGCC repeats associated with C9ORF72 can be translated in an ATG-independent manner (without an ATG start codon) known as repeat-associated non-ATG (RAN) translation (<a href="#24" class="mim-tip-reference" title="Mori, K., Weng, S.-M., Arzberger, T., May, S., Rentzsch, K., Kremmer, E., Schmid, B., Kretzschmar, H. A., Cruts, M., Van Broeckhoven, C., Haass, C., Edbauer, D. <strong>The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS.</strong> Science 339: 1335-1338, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23393093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23393093</a>] [<a href="https://doi.org/10.1126/science.1232927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23393093">Mori et al., 2013</a>). The translation products of the sense and antisense transcripts of the expansion repeats associated with the C9ORF72 gene altered in neurodegenerative disease encode glycine:arginine (GR(n)) and proline:arginine (PR(n)) repeat polypeptides, respectively. <a href="#19" class="mim-tip-reference" title="Kwon, I., Xiang, S., Kato, M., Wu, L., Theodoropoulos, P., Wang, T., Kim, J., Yun, J., Xie, Y., McKnight, S. L. <strong>Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells.</strong> Science 345: 1139-1145, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25081482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25081482</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25081482[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.1254917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25081482">Kwon et al. (2014)</a> found that both peptides bound to hnRNPA2 (see <a href="/entry/600124">600124</a>) hydrogels. When applied to cultured cells, both GR(20) and PR(20) peptides entered cells, migrated to the nucleus, bound nucleoli, and poisoned RNA biogenesis, which caused cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25081482+23393093" 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="Mizielinska, S., Gronke, S., Niccoli, T., Ridler, C. E., Clayton, E. L., Devoy, A., Moens, T., Norona, F. E., Woollacott, I. O. C., Pietrzyk, J., Cleverley, K., Nicoll, A. J., Pickering-Brown, S., Dols, J., Cabecinha, M., Hendrich, O., Fratta, P., Fisher, E. M. C., Partridge, L., Isaacs, A. M. <strong>C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins.</strong> Science 345: 1192-1194, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25103406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25103406</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25103406[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.1256800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25103406">Mizielinska et al. (2014)</a> developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats, but not stop codon-interrupted 'RNA-only' repeats, in Drosophila caused adult-onset neurodegeneration. Thus, expanded repeats promoted neurodegeneration through dipeptide repeat proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence revealed that both poly-(glycine-arginine; GR) and poly-(proline-arginine; PR) proteins caused neurodegeneration. <a href="#22" class="mim-tip-reference" title="Mizielinska, S., Gronke, S., Niccoli, T., Ridler, C. E., Clayton, E. L., Devoy, A., Moens, T., Norona, F. E., Woollacott, I. O. C., Pietrzyk, J., Cleverley, K., Nicoll, A. J., Pickering-Brown, S., Dols, J., Cabecinha, M., Hendrich, O., Fratta, P., Fisher, E. M. C., Partridge, L., Isaacs, A. M. <strong>C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins.</strong> Science 345: 1192-1194, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25103406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25103406</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25103406[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.1256800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25103406">Mizielinska et al. (2014)</a> concluded that their findings were consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9ORF72-mediated neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25103406" 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>To discover RNA-binding proteins that genetically modify GGGGCC (G4C2)-mediated neurogenesis, <a href="#37" class="mim-tip-reference" title="Zhang, K., Donnelly, C. J., Haeusler, A. R., Grima, J. C., Machamer, J. B., Steinwald, P., Daley, E. L., Miller, S. J., Cunningham, K. M., Vidensky, S., Gupta, S., Thomas, M. A., and 9 others. <strong>The C9orf72 repeat expansion disrupts nucleocytoplasmic transport.</strong> Nature 525: 56-61, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26308891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26308891</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26308891[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/nature14973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26308891">Zhang et al. (2015)</a> performed a candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats. They identified RanGAP (the Drosophila ortholog of human RanGAP1, <a href="/entry/602362">602362</a>), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppressed neurodegeneration. RanGAP physically interacted with HRE RNA and was mislocalized in HRE-expressing flies, neurons from C9ORF72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9ORF72 ALS patient brain tissue. Nuclear import was impaired as a result of HRE expression in the fly model and in C9ORF72 iPSC-derived neurons, and these deficits were rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. <a href="#37" class="mim-tip-reference" title="Zhang, K., Donnelly, C. J., Haeusler, A. R., Grima, J. C., Machamer, J. B., Steinwald, P., Daley, E. L., Miller, S. J., Cunningham, K. M., Vidensky, S., Gupta, S., Thomas, M. A., and 9 others. <strong>The C9orf72 repeat expansion disrupts nucleocytoplasmic transport.</strong> Nature 525: 56-61, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26308891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26308891</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26308891[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/nature14973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26308891">Zhang et al. (2015)</a> suggested that nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26308891" 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="Freibaum, B. D., Lu, Y., Lopez-Gonzalez, R., Kim, N. C., Almeida, S., Lee, K.-H., Badders, N., Valentine, M., Miller, B. L., Wong, P. C., Petrucelli, L., Kim, H. J., Gao, F.-B., Taylor, J. P. <strong>GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport.</strong> Nature 525: 129-133, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26308899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26308899</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26308899[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/nature14974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26308899">Freibaum et al. (2015)</a> independently generated transgenic flies expressing 8, 28, or 58 G4C2 repeat-containing transcripts that did not have a translation start site but contained an open reading frame for green fluorescent protein to detect repeat-associated non-AUG (RAN) translation. <a href="#13" class="mim-tip-reference" title="Freibaum, B. D., Lu, Y., Lopez-Gonzalez, R., Kim, N. C., Almeida, S., Lee, K.-H., Badders, N., Valentine, M., Miller, B. L., Wong, P. C., Petrucelli, L., Kim, H. J., Gao, F.-B., Taylor, J. P. <strong>GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport.</strong> Nature 525: 129-133, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26308899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26308899</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26308899[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/nature14974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26308899">Freibaum et al. (2015)</a> showed that these transgenic animals display dosage-dependent, repeat length-dependent degeneration in neuronal tissues and RAN translation of dipeptide repeat proteins, as observed in patients with C9ORF72-related disease. This model was used in a large-scale, unbiased genetic screen, ultimately leading to the identification of 18 genetic modifiers that encode components of the nuclear pore complex (NPC), as well as the machinery that coordinates the export of nuclear RNA and the import of nuclear proteins. Consistent with these results, <a href="#13" class="mim-tip-reference" title="Freibaum, B. D., Lu, Y., Lopez-Gonzalez, R., Kim, N. C., Almeida, S., Lee, K.-H., Badders, N., Valentine, M., Miller, B. L., Wong, P. C., Petrucelli, L., Kim, H. J., Gao, F.-B., Taylor, J. P. <strong>GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport.</strong> Nature 525: 129-133, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26308899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26308899</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26308899[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/nature14974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26308899">Freibaum et al. (2015)</a> found morphologic abnormalities in the architecture of the nuclear envelope in cells expressing expanded G4C2 repeats in vitro and in vivo. Moreover, the authors identified a substantial defect in RNA export resulting in retention of RNA in the nuclei of Drosophila cells expressing expanded G4C2 repeats and also in mammalian cells, including aged induced pluripotent stem cell-derived neurons from patients with C9ORF72-related disease. <a href="#13" class="mim-tip-reference" title="Freibaum, B. D., Lu, Y., Lopez-Gonzalez, R., Kim, N. C., Almeida, S., Lee, K.-H., Badders, N., Valentine, M., Miller, B. L., Wong, P. C., Petrucelli, L., Kim, H. J., Gao, F.-B., Taylor, J. P. <strong>GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport.</strong> Nature 525: 129-133, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26308899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26308899</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26308899[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/nature14974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26308899">Freibaum et al. (2015)</a> concluded that their studies showed that a primary consequence of G4C2 repeat expansion is the compromise of nucleocytoplasmic transport through the nuclear pore, revealing a novel mechanism of neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26308899" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using mass spectrometric analysis, <a href="#29" class="mim-tip-reference" title="Sellier, C., Campanari, M.-L., Corbier, C. J., Gaucherot, A., Kolb-Cheynel, I., Oulad-Abdelghani, M., Ruffenach, F., Page, A., Ciura, S., Kabashi, E., Charlet-Berguerand, N. <strong>Loss of C9ORF72 impairs autophagy and synergizes with polyQ ataxin-2 to induce motor neuron dysfunction and cell death.</strong> EMBO J. 35: 1276-1297, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27103069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27103069</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27103069[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/10.15252/embj.201593350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27103069">Sellier et al. (2016)</a> identified several proteins that purified with epitope-tagged human C9ORF72 following transfection of mouse N2A cells, including Rab8a (<a href="/entry/165040">165040</a>), Rab39b (<a href="/entry/300774">300774</a>), Smcr8 (<a href="/entry/617074">617074</a>), Wdr41 (<a href="/entry/617502">617502</a>), p62 (SQSTM1; <a href="/entry/601530">601530</a>), Hsc70 (HSPA8; <a href="/entry/600816">600816</a>), Hsp90 (see <a href="/entry/140571">140571</a>), and Bag3 (<a href="/entry/603883">603883</a>). Coimmunoprecipitation analysis of human constructs confirmed direct interaction between the long, but not short, isoform of C9ORF72 with SMCR8 and WDR41. The 3 proteins functioned as a GDP-GTP exchange factor for RAB8A and RAB39B, which are small GTPases involved in vesicle trafficking and autophagy. Knockdown of C9orf72, Smcr8, or Wdr41 in cultured mouse cortical neurons inhibited autophagy and led to accumulation of cytoplasmic aggregates of p62 and Tdp43 (TARDBP; <a href="/entry/605078">605078</a>), and failure to lipidate Lc3b (MAP1LC3B; <a href="/entry/609604">609604</a>), which is required for formation of autophagic vesicles. Knockdown of C9orf72 also potentiated aggregation and neurotoxicity of ataxin-2 (ATXN2; <a href="/entry/601517">601517</a>) with intermediate length of polyglutamine expansion (Q30x), but did not induce aggregation and toxicity in wildtype ataxin-2. <a href="#29" class="mim-tip-reference" title="Sellier, C., Campanari, M.-L., Corbier, C. J., Gaucherot, A., Kolb-Cheynel, I., Oulad-Abdelghani, M., Ruffenach, F., Page, A., Ciura, S., Kabashi, E., Charlet-Berguerand, N. <strong>Loss of C9ORF72 impairs autophagy and synergizes with polyQ ataxin-2 to induce motor neuron dysfunction and cell death.</strong> EMBO J. 35: 1276-1297, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27103069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27103069</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27103069[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/10.15252/embj.201593350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27103069">Sellier et al. (2016)</a> concluded that C9ORF72, SMCR8, and WDR41 interact in a complex that regulates autophagy and clears deleterious protein aggregates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27103069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a proteomic screen followed by coimmunoprecipitation analysis, <a href="#33" class="mim-tip-reference" title="Sullivan, P. M., Zhou, X., Robins, A. M., Paushter, D. H., Kim, D., Smolka, M. B., Hu, F. <strong>The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway.</strong> Acta Neuropath. Commun. 4: 51, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27193190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27193190</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27193190[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/s40478-016-0324-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27193190">Sullivan et al. (2016)</a> independently found that the long isoform of C9ORF72 interacted with SMCR8. The C9ORF72-SMCR8 heterodimer also interacted with the Golgi complex membrane protein WDR41. Furthermore, the C9ORF72-SMCR8-WDR41 trimer associated with the FIP200 (RB1CC1; <a href="/entry/606837">606837</a>)-ULK1 (<a href="/entry/603168">603168</a>)-ATG13 (<a href="/entry/615088">615088</a>)-ATG10 (<a href="/entry/610800">610800</a>) complex, which is essential for autophagy initiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27193190" 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 genome-editing strategies with human cells, <a href="#1" class="mim-tip-reference" title="Amick, J., Roczniak-Ferguson, A., Ferguson, S. M. <strong>C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling.</strong> Molec. Biol. Cell 27: 3040-3051, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27559131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27559131</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27559131[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1091/mbc.E16-01-0003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27559131">Amick et al. (2016)</a> found that C9ORF72 robustly interacted with SMCR8. C9ORF72 localized to lysosomes, and this localization was negatively regulated by amino acid availability. Studies of knockout cells revealed phenotypes that supported a role for C9ORF72 at lysosomes, including lysosomes swelling in the absence of C9ORF72 and impaired responses of mTORC1 (<a href="/entry/601231">601231</a>) signaling to changes in amino acid availability due to depletion of C9ORF72 or SMCR8. <a href="#1" class="mim-tip-reference" title="Amick, J., Roczniak-Ferguson, A., Ferguson, S. M. <strong>C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling.</strong> Molec. Biol. Cell 27: 3040-3051, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27559131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27559131</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27559131[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1091/mbc.E16-01-0003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27559131">Amick et al. (2016)</a> concluded that C9ORF72 and SMCR8 have strong physical and functional interactions at lysosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27559131" 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 proteomic and immunoprecipitation analyses, <a href="#10" class="mim-tip-reference" title="Ciura, S., Sellier, C., Campanari, M.-L., Charlet-Berguerand, N., Kabashi, E. <strong>The most prevalent genetic cause of ALS-FTD, C9orf72 synergizes the toxicity of ATXN2 intermediate polyglutamine repeats through the autophagy pathway.</strong> Autophagy 12: 1406-1408, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27245636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27245636</a>] [<a href="https://doi.org/10.1080/15548627.2016.1189070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27245636">Ciura et al. (2016)</a> found that C9ORF72 existed in a complex with SMCR8 and WDR41. The complex acted as GDP/GTP exchange factor for RAB8 and RAB39, which are involved in autophagy. C9ORF72 depletion in neuronal cell cultures led to accumulation of unresolved aggregates of SQSTM1 and phosphorylated TARDBP, but it did not result in major neuronal toxicity. Coexpression of intermediate polyglutamine repeats (30Q) within ATXN2 combined with C9ORF72 depletion increased aggregation of ATXN2 and neuronal toxicity. <a href="#10" class="mim-tip-reference" title="Ciura, S., Sellier, C., Campanari, M.-L., Charlet-Berguerand, N., Kabashi, E. <strong>The most prevalent genetic cause of ALS-FTD, C9orf72 synergizes the toxicity of ATXN2 intermediate polyglutamine repeats through the autophagy pathway.</strong> Autophagy 12: 1406-1408, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27245636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27245636</a>] [<a href="https://doi.org/10.1080/15548627.2016.1189070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27245636">Ciura et al. (2016)</a> concluded that C9ORF72 plays an important role in the autophagy pathway and interacts genetically with ATXN2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27245636" 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 HEK293 cells, <a href="#36" class="mim-tip-reference" title="Yang, M., Liang, C., Swaminathan, K., Herrlinger, S., Lai, F., Shiekhattar, R., Chen, J.-F. <strong>A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy.</strong> Sci. Adv. 2: e1601167, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27617292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27617292</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27617292[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/sciadv.1601167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27617292">Yang et al. (2016)</a> observed interaction of C9ORF72 with SMCR8, WDR41, and ATG101 (<a href="/entry/615089">615089</a>) and found that this complex associated with the ULK1 complex. The C9ORF72 complex exhibited GTPase activity and acted as a guanine nucleotide exchange factor for RAB39B. In mouse neuroblastoma cells, interaction of C9orf72 with Smcr8 depended on the DENN domains of each protein. Mouse cells deficient in Smcr8 had a reduced capacity to induce autophagy. Autophagy induction was compromised by knockdown of C9orf72 and was also disrupted in cells lacking both C9orf72 and Smcr8. In HEK293 cells, the C9ORF72/SMCR8 complex interacted with the ULK1/ATG13 complex, and this interaction was facilitated by amino acid starvation. Expression of Ulk1 was enhanced in mouse cells lacking Smcr8, but not in cells lacking C9orf72. Moreover, autophagic flux was defective in Smcr8-deficient cells, but it was increased by knockdown of C9orf72. <a href="#36" class="mim-tip-reference" title="Yang, M., Liang, C., Swaminathan, K., Herrlinger, S., Lai, F., Shiekhattar, R., Chen, J.-F. <strong>A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy.</strong> Sci. Adv. 2: e1601167, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27617292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27617292</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27617292[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/sciadv.1601167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27617292">Yang et al. (2016)</a> concluded that C9ORF72 and SMCR8 have roles in modulating autophagy induction by regulating ULK1, but that they play distinct roles in regulating autophagic flux. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27617292" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Kramer, N. J., Carlomagno, Y., Zhang, Y.-J., Almeida, S., Cook, C. N., Gendron, T. F., Prudencio, M., Van Blitterswijk, M., Belzil, V., Couthouis, J., Paul, J. W., III, Goodman, L. D., and 24 others. <strong>Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts.</strong> Science 353: 708-712, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27516603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27516603</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27516603[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.aaf7791" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27516603">Kramer et al. (2016)</a> found that targeting Spt4 selectively decreased production of both sense and antisense expanded transcripts of C9orf72, as well as their translated dipeptide repeat (DPR) products, and also mitigated degeneration in animal models. Knockdown of SUPT4H1 (<a href="/entry/603555">603555</a>), the human Spt4 ortholog, similarly decreased production of sense and antisense RNA foci and DPR proteins in patient cells. The authors argued that single-factor targeting has advantages over targeting sense and antisense repeats separately. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27516603" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Chang, Y.-J., Jeng, U-S., Chiang, Y.-L., Hwang, I.-S., Chen, Y.-R. <strong>The glycine-alanine dipeptide repeat from C9orf72 hexanucleotide expansions forms toxic amyloids possessing cell-to-cell transmission properties.</strong> J. Biol. Chem. 291: 4903-4911, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26769963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26769963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26769963[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.M115.694273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26769963">Chang et al. (2016)</a> found that a synthetic glycine-alanine (GA) DPR from C9ORF72 with 15 repeats , referred to as (GA)15, rapidly formed amyloid fibrils, starting with formation of short filaments and, later, ribbon-type fibrils. (GA)15 aggregates were neurotoxic and exhibited cell-to-cell transmission properties in which the aggregates could be taken from the extracellular space and transmitted among human neuroblastoma cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26769963" 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 proteomic analysis, <a href="#20" class="mim-tip-reference" title="Lee, K.-H., Zhang, P., Kim, H. J., Mitrea, D. M., Sarkar, M., Freibaum, B. D., Cika, J., Coughlin, M., Messing, J., Molliex, A., Maxwell, B. A., Kim, N. C., Temirov, J., Moore, J., Kolaitis, R.-M., Shaw, T. I., Bai, B., Peng, J., Kriwacki, R. W., Taylor, J. P. <strong>C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles.</strong> Cell 167: 774-788, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27768896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27768896</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27768896[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2016.10.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27768896">Lee et al. (2016)</a> showed that DPR species containing arginine (GR and PR) produced from hexanucleotide repeat expansion in C9ORF72 shared a common set of interactors enriched in low complexity sequence domains (LCDs) in HEK293T cells. Most GR and PR interactors were components of membraneless organelles, with some overlap between interactors of GR/PR and those identified in flies expressing an expanded G4C2 repeat. Toxicity test revealed that these arginine-containing DPRs were particularly toxic in Drosophila and mammalian cells. In vitro and live-cell analyses with HeLa cells showed that GR and PR DPRs localized to nucleolar substructures and impaired biophysical properties of NPM1 (<a href="/entry/164040">164040</a>), thereby disrupting nucleolar dynamics and impairing nucleolar function. In living cells, GR and PR DPRs interacted with stress granule proteins and altered stress granule dynamics by promoting spontaneous assembly of poorly dynamic stress granules. GR and PR also inhibited cellular translation by directly interacting with LCD-containing RNA-binding proteins and altering their biophysical properties. Arginine-containing DPRs also impaired the assembly or dynamics of other membraneless organelles, such as nuclear speckles and Cajal bodies, in living cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27768896" 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="Joung, J., Engreitz, J. M., Konermann, S., Abudayyeh, O. O., Verdine, V. K., Aguet, F., Gootenberg, J. S., Sanjana, N. E., Wright, J. B., Fulco, C. P., Tseng, Y.-Y., Yoon, C. H., Boehm, J. S., Lander, E. S., Zhang, F. <strong>Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhood.</strong> Nature 548: 343-346, 2017. Note: Erratum: Nature 549: 418 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28792927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28792927</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28792927[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/nature23451" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28792927">Joung et al. (2017)</a> found that activation of the long noncoding RNA EMICERI (<a href="/entry/617651">617651</a>) resulted in dose-dependent activation of its neighboring genes, including EQTN (<a href="/entry/617653">617653</a>), MOB3B (<a href="/entry/617652">617652</a>), IFNK (<a href="/entry/615326">615326</a>), and CORF72. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28792927" 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="Kramer, N. J., Haney, M. S., Morgens, D. W. , Jovicic, A., Couthouis, J., Li, A., Ousey, J., Ma, R., Bieri, G., Tsui, C. K., Shi, Y., Hertz, N. T., Tessier-Lavigne, M., Ichida, J. K., Bassik, M. C., Gitler, A. D. <strong>CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.</strong> Nature Genet. 50: 603-612, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29507424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29507424</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29507424[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/s41588-018-0070-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29507424">Kramer et al. (2018)</a> noted that C9ORF72 DPR proteins induce an endoplasmic reticulum (ER) stress response. Using genomewide CRISPR-Cas9 knockout screens in the human cell line K562, followed by secondary CRISPR-Cas9 screens in primary mouse neurons, <a href="#18" class="mim-tip-reference" title="Kramer, N. J., Haney, M. S., Morgens, D. W. , Jovicic, A., Couthouis, J., Li, A., Ousey, J., Ma, R., Bieri, G., Tsui, C. K., Shi, Y., Hertz, N. T., Tessier-Lavigne, M., Ichida, J. K., Bassik, M. C., Gitler, A. D. <strong>CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.</strong> Nature Genet. 50: 603-612, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29507424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29507424</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29507424[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/s41588-018-0070-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29507424">Kramer et al. (2018)</a> uncovered modifiers of C9ORF72 DPR toxicity, including Tmx2 (<a href="/entry/616715">616715</a>), an ER-resident transmembrane thioredoxin protein. Tmx2 was found to modulate the C9ORF72 DPR-induced ER-stress response in neurons and to improve the survival of human-induced motor neuronal cells from C9ORF72 ALS patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29507424" 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 genomewide knockout screens in human cells, <a href="#7" class="mim-tip-reference" title="Cheng, W., Wang, S., Zhang, Z., Morgens, D. W., Hayes, L. R., Lee, S., Portz, B., Xie, Y., Nguyen, B. V., Haney, M. S., Yan, S., Dong, D., and 10 others. <strong>CRISPR-Cas9 screens identify the RNA helicase DDX3X as a repressor of C9ORF72 (GGGGCC)n repeat-associated non-AUG translation.</strong> Neuron 104: 885-898, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31587919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31587919</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31587919[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2019.09.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31587919">Cheng et al. (2019)</a> showed that the NXF1 (<a href="/entry/602647">602647</a>)-NXT1 (<a href="/entry/605811">605811</a>) pathway mediated nuclear export of C9ORF72 GGGGCC repeat-containing RNA to the cytoplasm for translation, thereby influencing C9ORF72 DPR protein production. The RNA helicase DDX3X (<a href="/entry/300160">300160</a>) was identified as a modifier of DPR protein production, as it suppressed RAN translation of C9ORF72 (GGGGCC)n repeats by directly and selectively binding to GGGGCC repeat RNA. Binding to GGGGCC repeat RNA activated DDX3X ATPase activity for RNA structure unwinding, and translation repression required DDX3X helicase activity. Similarly, loss of Bel, the Drosophila ortholog of DDX3X, enhanced GGGGCC repeat toxicity in Drosophila, whereas ectopic expression of Bel partially rescued it, identifying Bel as a genetic modifier of GGGGCC repeat-mediated toxicity in vivo. ELISA revealed that DDX3X expression modulated repeat-mediated toxicity in ALS patient cells by regulating DPR production from RAN translation <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31587919" 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="Ortega, J. A., Daley, E. L., Kour, S., Samani, M., Tellez, L., Smith, H. S., Hall, E. A., Esengul, Y. T., Tsai, Y.-H., Gendron, T. F., Donnelly, C. J., Siddique, T., Savas, J. N., Pandey, U. B., Kiskinis, E. <strong>Nucleocytoplasmic proteomic analysis uncovers eRF1 and nonsense-mediated decay as modifiers of ALS/FTD C9orf72 toxicity.</strong> Neuron 106: 90-107, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32059759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32059759</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32059759[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2020.01.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32059759">Ortega et al. (2020)</a> found that the hexanucleotide repeat expansion in C9ORF72 (<a href="#0001">614260.0001</a>) associated with autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis (FTDALS1; <a href="/entry/105550">105550</a>) led to proteome-wide nucleocytoplasmic redistribution, with more proteins accumulating in cytoplasm. Analysis with a Drosophila disease model identified Erf1 (ETF1; <a href="/entry/600285">600285</a>) as a genetic interactor of mutant C9orf72 toxicity, and ERF1 was among the proteins that exhibited a significant magnitude of change in localization in association with the C9ORF72 repeat expansion. Analysis with motor neurons derived from pluripotent stem cells confirmed that ERF1 was redistributed in motor neurons and postmortem tissue of ALS patients with a C9ORF72 repeat expansion. Redistribution of ERF1 resulted in a functional shift of EFR1 from protein translation to nonsense-mediated decay (NMD) of mRNA molecules. This functional shift of EFR1 targeted C9ORF72 mRNA and induced UPF1 (<a href="/entry/601430">601430</a>)-dependent degradation of the expanded C9ORF72 transcript, thereby conferring a protective effect against toxicity of the C9ORF72 repeat expansion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32059759" 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="Zhang, Y.-J., Guo, L., Gonzales, P. K., Gendron, T. F., Wu, Y., Jansen-West, K., O'Raw, A. D., Pickles, S. R., Prudencio, M., Carlomagno, Y., Gachechiladze, M. A., Ludwig, C., and 23 others. <strong>Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity.</strong> Science 363: eaav2606, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30765536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30765536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30765536[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.aav2606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30765536">Zhang et al. (2019)</a> developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded C9ORF72 GGGGCC (G4C2) repeats. The expression of green fluorescent protein-conjugated (PR)50 (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. <a href="#38" class="mim-tip-reference" title="Zhang, Y.-J., Guo, L., Gonzales, P. K., Gendron, T. F., Wu, Y., Jansen-West, K., O'Raw, A. D., Pickles, S. R., Prudencio, M., Carlomagno, Y., Gachechiladze, M. A., Ludwig, C., and 23 others. <strong>Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity.</strong> Science 363: eaav2606, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30765536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30765536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30765536[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.aav2606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30765536">Zhang et al. (2019)</a> found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1a (HP1a; <a href="/entry/604478">604478</a>) liquid-phase disruptions, decreases in HP1a expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1a, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. <a href="#38" class="mim-tip-reference" title="Zhang, Y.-J., Guo, L., Gonzales, P. K., Gendron, T. F., Wu, Y., Jansen-West, K., O'Raw, A. D., Pickles, S. R., Prudencio, M., Carlomagno, Y., Gachechiladze, M. A., Ludwig, C., and 23 others. <strong>Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity.</strong> Science 363: eaav2606, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30765536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30765536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30765536[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.aav2606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30765536">Zhang et al. (2019)</a> concluded that they uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of C9ORF72-associated FTD and ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30765536" 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="McCauley, M. E., O'Rourke, J. G., Yanez, A., Markman, J. L., Ho, R., Wang, X., Chen, S., Lall, D., Jin, M., Muhammad, A. K. M. G., Bell, S., Laderos, J., Valencia, V., Harms, M., Arditi, M., Jefferies, C., Baloh, R. H. <strong>C9orf72 in myeloid cells suppresses STING-induced inflammation.</strong> Nature 585: 96-101, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32814898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32814898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32814898[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/s41586-020-2625-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32814898">McCauley et al. (2020)</a> found that blood-derived macrophages, whole blood, and brain tissue from patients with FTDALS1 exhibited an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD. Moreover, this increased interferon response could be suppressed with an inhibitor of STING (<a href="/entry/612374">612374</a>), a key regulator of the innate immune response to cytosolic DNA. <a href="#21" class="mim-tip-reference" title="McCauley, M. E., O'Rourke, J. G., Yanez, A., Markman, J. L., Ho, R., Wang, X., Chen, S., Lall, D., Jin, M., Muhammad, A. K. M. G., Bell, S., Laderos, J., Valencia, V., Harms, M., Arditi, M., Jefferies, C., Baloh, R. H. <strong>C9orf72 in myeloid cells suppresses STING-induced inflammation.</strong> Nature 585: 96-101, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32814898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32814898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32814898[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/s41586-020-2625-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32814898">McCauley et al. (2020)</a> concluded that these findings, as well as their findings in C9orf72 mutant mice (see ANIMAL MODEL), suggested that patients with FTDALS1 have an altered immunophenotype because reduced levels of C9ORF72 cannot suppress inflammation mediated by induction of type I interferons by STING. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32814898" 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="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://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, TBK1 (<a href="/entry/604834">604834</a>), and TDP43 (<a href="/entry/605078">605078</a>). <a href="#30" 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://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>
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<p>In affected members of large families with autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis mapping to chromosome 9p21 (FTDALS1; <a href="/entry/105550">105550</a>), <a href="#11" class="mim-tip-reference" title="DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., Kouri, N., Wojtas, A., and 16 others. <strong>Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.</strong> Neuron 72: 245-256, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944778</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944778[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944778">DeJesus-Hernandez et al. (2011)</a> and <a href="#28" class="mim-tip-reference" title="Renton, A. E., Majounie, E., Waite, A., Simon-Sanchez, J., Rollinson, S., Gibbs, J. R., Schymick, J. C., Laaksovirta, H., van Swieten, J. C., Myllykangas, L., Kalimo, H., Paetau, A., and 65 others. <strong>A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.</strong> Neuron 72: 257-268, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944779</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944779[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944779">Renton et al. (2011)</a> simultaneously and independently identified a heterozygous expanded hexanucleotide repeat (GGGGCC) located between the noncoding exons 1a and 1b of the C9ORF72 gene (<a href="#0001">614260.0001</a>). The maximum size of the repeat in healthy controls was 23 units, whereas it was expanded to 700 to 1,600 (<a href="#11" class="mim-tip-reference" title="DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., Kouri, N., Wojtas, A., and 16 others. <strong>Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.</strong> Neuron 72: 245-256, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944778</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944778[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944778">DeJesus-Hernandez et al., 2011</a>) or 250 repeats (<a href="#28" class="mim-tip-reference" title="Renton, A. E., Majounie, E., Waite, A., Simon-Sanchez, J., Rollinson, S., Gibbs, J. R., Schymick, J. C., Laaksovirta, H., van Swieten, J. C., Myllykangas, L., Kalimo, H., Paetau, A., and 65 others. <strong>A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.</strong> Neuron 72: 257-268, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944779</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944779[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944779">Renton et al., 2011</a>) in patients. <a href="#11" class="mim-tip-reference" title="DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., Kouri, N., Wojtas, A., and 16 others. <strong>Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.</strong> Neuron 72: 245-256, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944778</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944778[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944778">DeJesus-Hernandez et al. (2011)</a> identified this expanded hexanucleotide repeat in 16 (61.5%) of a series of 26 families with the disorder, as well as in 11.7% of familial FTD and 23.5% of familial ALS from 3 patient series. Sporadic cases with the expansion were also identified. Overall, 75 (10.4%) of 722 unrelated patients with FTD, ALS, or both were found to carry an expanded GGGGCC repeat. <a href="#28" class="mim-tip-reference" title="Renton, A. E., Majounie, E., Waite, A., Simon-Sanchez, J., Rollinson, S., Gibbs, J. R., Schymick, J. C., Laaksovirta, H., van Swieten, J. C., Myllykangas, L., Kalimo, H., Paetau, A., and 65 others. <strong>A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.</strong> Neuron 72: 257-268, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944779</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944779[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944779">Renton et al. (2011)</a> found the expanded repeat in 46.4% of Finnish familial ALS cases and in 21% of sporadic cases from Finland, as well as in 38.1% of 268 familial ALS probands of European origin. Both <a href="#11" class="mim-tip-reference" title="DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., Kouri, N., Wojtas, A., and 16 others. <strong>Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.</strong> Neuron 72: 245-256, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944778</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944778[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944778">DeJesus-Hernandez et al. (2011)</a> and <a href="#28" class="mim-tip-reference" title="Renton, A. E., Majounie, E., Waite, A., Simon-Sanchez, J., Rollinson, S., Gibbs, J. R., Schymick, J. C., Laaksovirta, H., van Swieten, J. C., Myllykangas, L., Kalimo, H., Paetau, A., and 65 others. <strong>A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.</strong> Neuron 72: 257-268, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944779</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944779[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944779">Renton et al. (2011)</a> concluded that it is the most common genetic abnormality in FTD/ALS. The expanded repeat is located in the promoter region of C9ORF72 transcript variant 1 and in intron 1 of transcript variants 2 and 3. In the study of <a href="#11" class="mim-tip-reference" title="DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., Kouri, N., Wojtas, A., and 16 others. <strong>Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.</strong> Neuron 72: 245-256, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944778</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944778[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944778">DeJesus-Hernandez et al. (2011)</a>, transcript-specific cDNA amplified from frozen frontal cortex brain tissue from an affected individual showed absence of the variant 1 transcribed from the mutant RNA, whereas transcription of variants 2 and 3 was normal. mRNA expression analysis of variant 1 was decreased to about 50% in lymphoblast cells from a patient and in frontal cortex samples from other patients. These findings were consistent with a loss-of-function mechanism. However, protein levels of these variants were similar to controls, and analysis of patient frontal cortex and spinal cord tissue showed that the transcribed expanded GGGGCC repeat formed nuclear RNA foci, suggesting a gain-of-function mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21944779+21944778" 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 repeat-primed PCR, <a href="#2" class="mim-tip-reference" title="Beck, J., Poulter, M., Hensman, D., Rohrer, J. D., Mahoney, C. J., Adamson, G., Campbell, T., Uphill, J., Borg, A., Fratta, P., Orrell, R. W., Malaspina, A., and 15 others. <strong>Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population.</strong> Am. J. Hum. Genet. 92: 345-353, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23434116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23434116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23434116[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.01.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23434116">Beck et al. (2013)</a> identified 96 repeat-primed PCR expansions in a large population- and patient-based cohort: there were 85 (2.9%) expansions among 2,974 patients with various neurodegenerative diseases and 11 (0.15%) expansions among 7,579 controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in patients was 800 to 4,400. Large expansions were also detected in the population controls. There were some differences in expansion size and morphology between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, supported multiple expansion events on the same haplotype background. The findings suggested that there may be a higher prevalence of expanded C9ORF72 repeat carriers than previously thought. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23434116" 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 2 methods, <a href="#35" class="mim-tip-reference" title="Xi, Z., Zinman, L., Moreno, D., Schymick, J., Liang, Y., Sato, C., Zheng, Y., Ghani, M., Dib, S., Keith, J., Robertson, J., Rogaeva, E. <strong>Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion.</strong> Am. J. Hum. Genet. 92: 981-989, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23731538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23731538</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23731538[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23731538">Xi et al. (2013)</a> investigated the CpG methylation profile of genomic DNA from the blood of individuals with ALS, including 37 G4C2 expansion carriers and 64 noncarriers, 76 normal controls, and family members of 7 ALS patients with the expansion. Hypermethylation of the CpG island 5-prime to the G4C2 repeat was associated with presence of the expansion (p less than 0.0001). A higher degree of methylation was significantly correlated with a shorter disease duration (p less than 0.01), associated with familial ALS (p = 0.009) and segregated with the expansion in 7 investigated families. Methylation changes were not detected in either normal or intermediate alleles (up to 43 repeats), raising the question of whether the cutoff of 30 repeats for pathologic alleles was adequate. The findings suggested that pathogenic repeat expansion of the G4C2 allele in C9ORF72 may lead to epigenetic changes, such as gene expression silencing, that may be associated with disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23731538" 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="#9" class="mim-tip-reference" title="Ciura, S., Lattante, S., Le Ber, I., Latouche, M., Tostivint, H., Brice, A., Kabashi, E. <strong>Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis.</strong> Ann. Neurol. 74: 180-187, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23720273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23720273</a>] [<a href="https://doi.org/10.1002/ana.23946" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23720273">Ciura et al. (2013)</a> found expression of the C9orf72 gene in the brain and spinal cord of zebrafish embryos. Morpholino knockdown of C9orf72 in zebrafish resulted in disrupted neuronal arborization and shortening of the motor neuron axons compared to controls, as well as motor deficits. These deficits were rescued upon overexpression of human C9orf72 mRNA transcripts. These results revealed a pathogenic consequence of decreased C9orf72 levels, supporting a loss of function mechanism of disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23720273" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Chew, J., Gendron, T. F., Prudencio, M., Sasaguri, H., Zhang, Y.-J., Castanedes-Casey, M., Lee, C. W., Jansen-West, K., Kurti, A., Murray, M. E., Bieniek, K. F., Bauer, P. O., and 15 others. <strong>C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits.</strong> Science 348: 1151-1154, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25977373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25977373</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25977373[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.aaa9344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25977373">Chew et al. (2015)</a> developed a mouse model to mimic both neuropathologic and clinical FTD/ALS phenotypes caused by mutations in the C9ORF72 gene. The authors expressed 66 G4C2 repeats (G4C2(66)) throughout the murine CNS via somatic brain transgenesis mediated by adeno-associated virus. The brains of 6-month-old mice contained nuclear RNA foci, inclusions of poly(Gly-Pro), poly(Gly-Ala), and poly(Gly-Arg) dipeptide repeat proteins, as well as TDP43 (<a href="/entry/605078">605078</a>) pathology. These mouse brains also exhibited cortical neuron and cerebellar Purkinje cell loss, astrogliosis, and decreased weight. The G4C2(66) mice also developed behavioral abnormalities similar to clinical symptoms of FTD/ALS caused by C9ORF72 mutations, including hyperactivity, anxiety, antisocial behavior, and motor deficits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25977373" 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="O'Rourke, J. G., Bogdanik, L., Yanez, A., Lall, D., Wolf, A. J., Muhammad, A. K. M. G., Ho, R., Carmona, S., Vit, J. P., Zarrow, J., Kim, K. J., Bell, S., Harms, M. B., Miller, T. M., Dangler, C. A., Underhill, D. M., Goodridge, H. S., Lutz, C. M., Baloh, R. H. <strong>C9orf72 is required for proper macrophage and microglial function in mice.</strong> Science 351: 1324-1329, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26989253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26989253</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26989253[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.aaf1064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26989253">O'Rourke et al. (2016)</a> found that 2 independent mouse lines lacking the C9orf72 ortholog in all tissues developed normally and aged without motor neuron disease. However, C90rf72 -/- mice developed progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells. Loss of C9orf72 led to lysosomal accumulation and altered immune responses in macrophages and microglia, with age-related neuroinflammation resembling C9ORF72-related ALS but not sporadic ALS human tissue. <a href="#25" class="mim-tip-reference" title="O'Rourke, J. G., Bogdanik, L., Yanez, A., Lall, D., Wolf, A. J., Muhammad, A. K. M. G., Ho, R., Carmona, S., Vit, J. P., Zarrow, J., Kim, K. J., Bell, S., Harms, M. B., Miller, T. M., Dangler, C. A., Underhill, D. M., Goodridge, H. S., Lutz, C. M., Baloh, R. H. <strong>C9orf72 is required for proper macrophage and microglial function in mice.</strong> Science 351: 1324-1329, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26989253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26989253</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26989253[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.aaf1064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26989253">O'Rourke et al. (2016)</a> concluded that C9ORF72 is required for normal myeloid cell function and proposed that altered microglial function may contribute to neurodegeneration in C9ORF72 expansion carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26989253" 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 CRISPR/Cas9 gene editing system, <a href="#33" class="mim-tip-reference" title="Sullivan, P. M., Zhou, X., Robins, A. M., Paushter, D. H., Kim, D., Smolka, M. B., Hu, F. <strong>The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway.</strong> Acta Neuropath. Commun. 4: 51, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27193190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27193190</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27193190[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/s40478-016-0324-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27193190">Sullivan et al. (2016)</a> created C9orf72 -/- mice, which showed no apparent growth defect, but had obvious lymph node and spleen enlargement that became more severe with age. Livers of C9orf72 -/- mice also showed some enlargement, but brains appeared normal. Western blot and immunohistochemical analysis of C9orf72 -/- lymph node, spleen, and liver showed increased content of factors involved in the autophagy/lysosomal pathway. <a href="#33" class="mim-tip-reference" title="Sullivan, P. M., Zhou, X., Robins, A. M., Paushter, D. H., Kim, D., Smolka, M. B., Hu, F. <strong>The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway.</strong> Acta Neuropath. Commun. 4: 51, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27193190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27193190</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27193190[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/s40478-016-0324-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27193190">Sullivan et al. (2016)</a> concluded that deficiency in C9orf72 causes a defect in autophagy, likely downstream of Ulk1 activation in autophagy initiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27193190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a zebrafish model, <a href="#10" class="mim-tip-reference" title="Ciura, S., Sellier, C., Campanari, M.-L., Charlet-Berguerand, N., Kabashi, E. <strong>The most prevalent genetic cause of ALS-FTD, C9orf72 synergizes the toxicity of ATXN2 intermediate polyglutamine repeats through the autophagy pathway.</strong> Autophagy 12: 1406-1408, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27245636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27245636</a>] [<a href="https://doi.org/10.1080/15548627.2016.1189070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27245636">Ciura et al. (2016)</a> showed that partial knockdown of C9orf72 combined with intermediate repeat expansion of Atxn2 caused locomotion deficits and abnormal axonal projections from spinal motor neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27245636" 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="Burberry, A., Wells, M. F., Limone, F., Couto, A., Smith, K. S., Keaney, J., Gillet, G., van Gastel, N., Wang, J.-Y., Pietilainen, O., Qian, M., Eggan, P., Cantrell, C., Mok, J., Kadiu, I., Scadden, DT., Eggan, K. <strong>C9orf72 suppresses systemic and neural inflammation induced by gut bacteria.</strong> Nature 582: 89-94, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32483373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32483373</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32483373[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/s41586-020-2288-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32483373">Burberry et al. (2020)</a> reported that an environment with reduced abundance of immune-stimulating bacteria protects C9orf72-mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathologic inflammatory response, <a href="#5" class="mim-tip-reference" title="Burberry, A., Wells, M. F., Limone, F., Couto, A., Smith, K. S., Keaney, J., Gillet, G., van Gastel, N., Wang, J.-Y., Pietilainen, O., Qian, M., Eggan, P., Cantrell, C., Mok, J., Kadiu, I., Scadden, DT., Eggan, K. <strong>C9orf72 suppresses systemic and neural inflammation induced by gut bacteria.</strong> Nature 582: 89-94, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32483373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32483373</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32483373[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/s41586-020-2288-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32483373">Burberry et al. (2020)</a> found that reducing the microbial burden in mutant mice with broad spectrum antibiotics, as well as transplanting gut microflora from a protective environment, attenuated inflammatory phenotypes, even after their onset. <a href="#5" class="mim-tip-reference" title="Burberry, A., Wells, M. F., Limone, F., Couto, A., Smith, K. S., Keaney, J., Gillet, G., van Gastel, N., Wang, J.-Y., Pietilainen, O., Qian, M., Eggan, P., Cantrell, C., Mok, J., Kadiu, I., Scadden, DT., Eggan, K. <strong>C9orf72 suppresses systemic and neural inflammation induced by gut bacteria.</strong> Nature 582: 89-94, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32483373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32483373</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32483373[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/s41586-020-2288-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32483373">Burberry et al. (2020)</a> concluded that their studies provided further evidence that the microbial composition of the gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32483373" 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="McCauley, M. E., O'Rourke, J. G., Yanez, A., Markman, J. L., Ho, R., Wang, X., Chen, S., Lall, D., Jin, M., Muhammad, A. K. M. G., Bell, S., Laderos, J., Valencia, V., Harms, M., Arditi, M., Jefferies, C., Baloh, R. H. <strong>C9orf72 in myeloid cells suppresses STING-induced inflammation.</strong> Nature 585: 96-101, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32814898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32814898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32814898[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/s41586-020-2625-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32814898">McCauley et al. (2020)</a> found that myeloid cell-specific loss of C9orf72 in mice was sufficient to recapitulate the age-dependent lymphoid hypertrophy and autoinflammation observed in C9orf72-knockout mice. Dendritic cells from C9orf72-knockout mice showed marked early activation of type I interferon response, and C9orf72-null myeloid cells were selectively hyperresponsive to activators of Sting. C9orf72-null myeloid cells exhibited diminished degradation of Sting through the autolysosomal pathway, and blocking Sting suppressed hyperactive type I interferon responses in C9orf72-null immune cells, as well as splenomegaly and inflammation in C9orf72-knockout mice. Moreover, mice lacking 1 or both copies of C9orf72 were more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune disease seen in people with FTDALS1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32814898" 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>.0001 FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 1</strong>
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C9ORF72, (GGGGCC)n REPEAT EXPANSION
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<p><a href="#11" class="mim-tip-reference" title="DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., Kouri, N., Wojtas, A., and 16 others. <strong>Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.</strong> Neuron 72: 245-256, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944778</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944778[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944778">DeJesus-Hernandez et al. (2011)</a> identified a polymorphic hexanucleotide repeat (GGGGCC) located between the noncoding exons 1a and 1b of the C9ORF72 gene. The maximum size of the repeat in healthy controls was 23 units, whereas it was expanded in members of a large family with frontotemporal dementia and/or amyotrophic lateral sclerosis mapping to chromosome 9p21 (FTDALS1; <a href="/entry/105550">105550</a>) (<a href="#4" class="mim-tip-reference" title="Boxer, A. L., Mackenzie, I. R., Boeve, B. F., Baker, M., Seeley, W. W., Crook, R., Feldman, H., Hsiung, G.-Y. R., Rutherford, N., Laluz, V., Whitwell, J., Foti, D., McDade, E., Molano, J., Karydas, A., Wojtas, A., Goldman, J., Mirsky, J., Sengdy, P., DeArmond, S., Miller, B. L., Rademakers, R. <strong>Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family.</strong> J. Neurol. Neurosurg. Psychiat. 82: 196-203, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20562461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20562461</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20562461[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jnnp.2009.204081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20562461">Boxer et al., 2011</a>). Affected individuals had expanded repeat units ranging from 700 to 1,600. Further analysis identified this expanded hexanucleotide repeat in 16 (61.5%) of a series of 26 families with the disorder, as well as in 11.7% of familial FTD and 23.5% of familial ALS from 3 patient series. Sporadic cases with the expansion were also identified. Overall, 75 (10.4%) of 722 unrelated patients with FTD, ALS, or both were found to carry an expanded GGGGCC repeat, and <a href="#11" class="mim-tip-reference" title="DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., Kouri, N., Wojtas, A., and 16 others. <strong>Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.</strong> Neuron 72: 245-256, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944778</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944778[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944778">DeJesus-Hernandez et al. (2011)</a> concluded that it is the most common genetic abnormality in FTD/ALS. Longer repeats were associated with the A allele at SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3849942;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3849942</a>, which marked a disease haplotype. The expanded repeat is located in the promoter region of C9ORF72 transcript variant 1 and in intron 1 of transcript variants 2 and 3. Tissue from affected individuals showed reduced or absent mRNA levels of C9ORF72 variants 1 and 3 compared to nonrepeat carriers, consistent with a loss-of-function mechanism. However, protein levels of these variants were similar to controls, and analysis of patient frontal cortex and spinal cord tissue showed that the transcribed expanded GGGGCC repeat formed nuclear RNA foci, suggesting a gain-of-function mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21944778+20562461" 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>Simultaneously and independently, <a href="#28" class="mim-tip-reference" title="Renton, A. E., Majounie, E., Waite, A., Simon-Sanchez, J., Rollinson, S., Gibbs, J. R., Schymick, J. C., Laaksovirta, H., van Swieten, J. C., Myllykangas, L., Kalimo, H., Paetau, A., and 65 others. <strong>A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.</strong> Neuron 72: 257-268, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944779</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944779[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944779">Renton et al. (2011)</a> identified the GGGGCC expanded repeat as a cause of FTD/ALS in families reported by <a href="#27" class="mim-tip-reference" title="Pearson, J. P., Williams, N. M., Majounie, E., Waite, A., Stott, J., Newsway, V., Murray, A., Hernandez, D., Guerreiro, R., Singleton, A. B., Neal, J., Morris, H. R. <strong>Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p.</strong> J. Neurol. 258: 647-655, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21072532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21072532</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21072532[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/s00415-010-5815-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21072532">Pearson et al. (2011)</a> and <a href="#23" class="mim-tip-reference" title="Mok, K., Traynor, B. J, Schymick, J., Tienari, P. J., Laaksovirta, H., Peuralinna, T., Myllykangas, L., Chio, A., Shatunov, A., Boeve, B. F., Boxer, A. L., DeJesus-Hernandez, M., and 18 others. <strong>The chromosome 9 ALS and FTD locus is probably derived from a single founder.</strong> Neurobiol. Aging 33: 209e3-209e8, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21925771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21925771</a>] [<a href="https://doi.org/10.1016/j.neurobiolaging.2011.08.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21925771">Mok et al. (2012)</a>. The expanded repeat was also found in 46.4% of Finnish familial ALS cases and in 21% of sporadic cases. PCR assays showed that Finnish controls had between 0 and 22 repeats. FISH studies showed that the expansion in a family from Wales (<a href="#27" class="mim-tip-reference" title="Pearson, J. P., Williams, N. M., Majounie, E., Waite, A., Stott, J., Newsway, V., Murray, A., Hernandez, D., Guerreiro, R., Singleton, A. B., Neal, J., Morris, H. R. <strong>Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p.</strong> J. Neurol. 258: 647-655, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21072532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21072532</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21072532[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/s00415-010-5815-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21072532">Pearson et al., 2011</a>) was at least 250 repeats. In addition, an expanded repeat was found in 102 (38.1%) of 268 familial ALS probands of European origin. Real-time RT-PCR analysis of expression in frontal cortex tissue from patients and controls did not detect conclusive changes in RNA levels and produced inconsistent results. Nevertheless, <a href="#28" class="mim-tip-reference" title="Renton, A. E., Majounie, E., Waite, A., Simon-Sanchez, J., Rollinson, S., Gibbs, J. R., Schymick, J. C., Laaksovirta, H., van Swieten, J. C., Myllykangas, L., Kalimo, H., Paetau, A., and 65 others. <strong>A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.</strong> Neuron 72: 257-268, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944779</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944779[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.09.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21944779">Renton et al. (2011)</a> postulated that a disruption in RNA metabolism likely underlies this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21944779+21925771+21072532" 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="Belzil, V. V., Daoud, H., Camu, W., Strong, M. J., Dion, P. A., Rouleau, G. A. <strong>Genetic analysis of SIGMAR1 as a cause of familial ALS with dementia.</strong> Europ. J. Hum. Genet. 21: 237-239, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22739338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22739338</a>] [<a href="https://doi.org/10.1038/ejhg.2012.135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22739338">Belzil et al. (2013)</a> identified a hexanucleotide repeat expansion in the C9ORF72 gene in 13 (52%) of 25 patients of Caucasian origin with ALS who had a family history of cognitive impairment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22739338" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="van der Zee, J., Gijselinck, I., Dillen, L., Van Langenhove, T., Theuns, J., Engelborghs, S., Philtjens, S., Vandenbulcke, M., Sleegers, K., Sieben, A., Baumer, V., Maes, G., and 50 others. <strong>A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats.</strong> Hum. Mutat. 34: 363-373, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23111906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23111906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23111906[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22244" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23111906">Van der Zee et al. (2013)</a> assessed the distribution of C9ORF72 G4C2 expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort of 1,205 individuals ascertained by the European Early-Onset Dementia (EOD) consortium. A metaanalysis of the data and that of other European studies, including a total of 2,668 patients from 15 countries, showed that the frequency of C9ORF72 expansions in Western Europe was 9.98% in FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of 29.33% and 20.73%, respectively, consistent with the hypothesis of a Scandinavian founder effect. However, Spain also showed a high frequency of the expansion, at 25.49%. In contrast, the prevalence in Germany was low, at 4.82%. The phenotype was most often characterized by behavioral disturbances (95.7%). Postmortem examination of a small number of cases showed TDP43 (<a href="/entry/605078">605078</a>) and p62 (<a href="/entry/601530">601530</a>) deposits in the brain. Intermediate repeats (7 to 24 repeat units) were found to be strongly correlated with the risk haplotype tagged by a T allele of SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2814707;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2814707</a>. In vitro reporter gene expression studies showed significantly decreased transcriptional activity of C9ORF72 with increasing number of normal repeat units, consistent with a loss of function. This was also observed with intermediate repeats, suggesting that they might act as predisposing alleles. There was also a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the expanded repeat in expansion carriers, suggesting that pathologic expansion may be due to replication slippage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23111906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Smith, B. N., Newhouse, S., Shatunov, A., Vance, C., Topp, S., Johnson, L., Miller, J., Lee, Y., Troakes, C., Scott, K. M., Jones, A., Gray, I., and 34 others. <strong>The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder.</strong> Europ. J. Hum. Genet. 21: 102-108, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22692064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22692064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22692064[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/ejhg.2012.98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22692064">Smith et al. (2013)</a> identified the expanded hexanucleotide repeat in C9ORF72 in 226 (17%) of 1,347 patients with ALS with or without FTD collected from 5 European populations in whom known ALS genes had been excluded. The expansion was also observed in 3 (0.3%) of 856 controls, yielding an odds ratio (OR) of 57 (p = 4.12 x 10(-47)), but also indicating incomplete penetrance. Haplotype analysis identified a common 82-SNP disease haplotype in the majority of 137 cases studied, indicating a single common founder in these European populations. The mutation was estimated to have arisen 6,300 years ago. The disease haplotype was found in almost 15% of European controls. The average number of pathogenic repeats on the disease haplotype was 8, with a spread of expanded alleles up to 26. The most prevalent number of repeats on other haplotypes was 2. The findings suggested that the background disease haplotype is intrinsically unstable, tending to generate longer repeats. The findings showed that the C9ORF72 expanded repeat is the most common genetic cause of ALS with or without FTD across Europe. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22692064" 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="#24" class="mim-tip-reference" title="Mori, K., Weng, S.-M., Arzberger, T., May, S., Rentzsch, K., Kremmer, E., Schmid, B., Kretzschmar, H. A., Cruts, M., Van Broeckhoven, C., Haass, C., Edbauer, D. <strong>The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS.</strong> Science 339: 1335-1338, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23393093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23393093</a>] [<a href="https://doi.org/10.1126/science.1232927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23393093">Mori et al. (2013)</a> found that most of the characteristic intracellular inclusions in ALS or FTLD caused by the C9orf72 hexanucleotide repeat expansion contain poly-(gly-ala) and, to a lesser extent poly-(gly-pro), and poly-(gly-arg) dipeptide repeat proteins presumably generated by non-ATG-initiated translation from the expanded GGGGCC repeat in 3 reading frames. <a href="#24" class="mim-tip-reference" title="Mori, K., Weng, S.-M., Arzberger, T., May, S., Rentzsch, K., Kremmer, E., Schmid, B., Kretzschmar, H. A., Cruts, M., Van Broeckhoven, C., Haass, C., Edbauer, D. <strong>The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS.</strong> Science 339: 1335-1338, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23393093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23393093</a>] [<a href="https://doi.org/10.1126/science.1232927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23393093">Mori et al. (2013)</a> concluded that their findings directly linked the FTLD/ALS-associated genetic mutation to the predominant pathology in patients with C9orf72 hexanucleotide expansion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23393093" 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="Gomez-Tortosa, E., Gallego, J., Guerrero-Lopez, R., Marcos, A., Gil-Neciga, E., Sainz, M. J., Diaz, A., Franco-Macias, E., Trujillo-Tiebas, M. J., Ayuso, C., Perez-Perez, J. <strong>C9ORF72 hexanucleotide expansions of 20-22 repeats are associated with frontotemporal deterioration.</strong> Neurology 80: 366-370, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23284068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23284068</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31827f08ea" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23284068">Gomez-Tortosa et al. (2013)</a> identified expanded C9ORF72 repeats in 9 (8.2%) of 109 Spanish probands with FTD. Four patients had more than 30 repeats, whereas 4 had 20 repeats and 1 had 22 repeats. None of the other 100 cases had greater than 13 repeats, and none of 216 controls had more than 14 repeats. In 4 families, the expanded 20- or 22-repeat alleles segregated consistently in all affected sibs, with the unaffected sibs having wildtype alleles (2-9 repeats). The 20- or 22-repeat allele was associated with the surrogate marker of the founder haplotype in all cases. Most of the 9 expansion carriers had extended periods with psychiatric symptoms and subjective cognitive complaints before clear neurologic deterioration, and there was no phenotypic difference between those with longer or shorter expansions. These findings suggested that short C9ORF72 hexanucleotide expansions in the 20- to 22-repeat range are also related to FTD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23284068" 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="1" class="mim-anchor"></a>
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<a id="Amick2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Amick, J., Roczniak-Ferguson, A., Ferguson, S. M.
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<strong>C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling.</strong>
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Molec. Biol. Cell 27: 3040-3051, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27559131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27559131</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27559131[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=27559131" 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/10.1091/mbc.E16-01-0003" target="_blank">Full Text</a>]
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</p>
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<a id="2" class="mim-anchor"></a>
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<a id="Beck2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Beck, J., Poulter, M., Hensman, D., Rohrer, J. D., Mahoney, C. J., Adamson, G., Campbell, T., Uphill, J., Borg, A., Fratta, P., Orrell, R. W., Malaspina, A., and 15 others.
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<strong>Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population.</strong>
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Am. J. Hum. Genet. 92: 345-353, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23434116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23434116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23434116[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=23434116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2013.01.011" target="_blank">Full Text</a>]
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</p>
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<a id="3" class="mim-anchor"></a>
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<a id="Belzil2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Belzil, V. V., Daoud, H., Camu, W., Strong, M. J., Dion, P. A., Rouleau, G. A.
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<strong>Genetic analysis of SIGMAR1 as a cause of familial ALS with dementia.</strong>
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Europ. J. Hum. Genet. 21: 237-239, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22739338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22739338</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22739338" 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/ejhg.2012.135" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="4" class="mim-anchor"></a>
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<a id="Boxer2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Boxer, A. L., Mackenzie, I. R., Boeve, B. F., Baker, M., Seeley, W. W., Crook, R., Feldman, H., Hsiung, G.-Y. R., Rutherford, N., Laluz, V., Whitwell, J., Foti, D., McDade, E., Molano, J., Karydas, A., Wojtas, A., Goldman, J., Mirsky, J., Sengdy, P., DeArmond, S., Miller, B. L., Rademakers, R.
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<strong>Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family.</strong>
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J. Neurol. Neurosurg. Psychiat. 82: 196-203, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20562461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20562461</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20562461[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=20562461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jnnp.2009.204081" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="5" class="mim-anchor"></a>
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<a id="Burberry2020" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Burberry, A., Wells, M. F., Limone, F., Couto, A., Smith, K. S., Keaney, J., Gillet, G., van Gastel, N., Wang, J.-Y., Pietilainen, O., Qian, M., Eggan, P., Cantrell, C., Mok, J., Kadiu, I., Scadden, DT., Eggan, K.
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<strong>C9orf72 suppresses systemic and neural inflammation induced by gut bacteria.</strong>
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Nature 582: 89-94, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32483373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32483373</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32483373[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=32483373" 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/s41586-020-2288-7" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="Chang2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Chang, Y.-J., Jeng, U-S., Chiang, Y.-L., Hwang, I.-S., Chen, Y.-R.
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<strong>The glycine-alanine dipeptide repeat from C9orf72 hexanucleotide expansions forms toxic amyloids possessing cell-to-cell transmission properties.</strong>
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J. Biol. Chem. 291: 4903-4911, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26769963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26769963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26769963[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=26769963" 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.M115.694273" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="Cheng2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Cheng, W., Wang, S., Zhang, Z., Morgens, D. W., Hayes, L. R., Lee, S., Portz, B., Xie, Y., Nguyen, B. V., Haney, M. S., Yan, S., Dong, D., and 10 others.
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<strong>CRISPR-Cas9 screens identify the RNA helicase DDX3X as a repressor of C9ORF72 (GGGGCC)n repeat-associated non-AUG translation.</strong>
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Neuron 104: 885-898, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31587919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31587919</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31587919[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=31587919" 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.neuron.2019.09.003" target="_blank">Full Text</a>]
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</p>
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<a id="8" class="mim-anchor"></a>
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<a id="Chew2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Chew, J., Gendron, T. F., Prudencio, M., Sasaguri, H., Zhang, Y.-J., Castanedes-Casey, M., Lee, C. W., Jansen-West, K., Kurti, A., Murray, M. E., Bieniek, K. F., Bauer, P. O., and 15 others.
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<strong>C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits.</strong>
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Science 348: 1151-1154, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25977373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25977373</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25977373[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=25977373" 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.aaa9344" target="_blank">Full Text</a>]
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</p>
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</div>
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<a id="9" class="mim-anchor"></a>
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<a id="Ciura2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ciura, S., Lattante, S., Le Ber, I., Latouche, M., Tostivint, H., Brice, A., Kabashi, E.
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<strong>Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis.</strong>
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Ann. Neurol. 74: 180-187, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23720273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23720273</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23720273" 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.23946" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Ciura2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ciura, S., Sellier, C., Campanari, M.-L., Charlet-Berguerand, N., Kabashi, E.
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<strong>The most prevalent genetic cause of ALS-FTD, C9orf72 synergizes the toxicity of ATXN2 intermediate polyglutamine repeats through the autophagy pathway.</strong>
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Autophagy 12: 1406-1408, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27245636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27245636</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27245636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1080/15548627.2016.1189070" target="_blank">Full Text</a>]
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</p>
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<a id="11" class="mim-anchor"></a>
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<a id="DeJesus-Hernandez2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., Kouri, N., Wojtas, A., and 16 others.
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<strong>Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.</strong>
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Neuron 72: 245-256, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21944778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21944778</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21944778[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=21944778" 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.neuron.2011.09.011" target="_blank">Full Text</a>]
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</p>
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<a id="12" class="mim-anchor"></a>
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<a id="Farg2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Farg, M. A., Sundaramoorthy, V., Sultana, J. M., Yang, S., Atkinson, R. A. K., Levina, V., Halloran, M. A., Gleeson, P. A., Blair, I. P., Soo, K. Y., King, A. E., Atkin, J. D.
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<strong>C9ORF72, implicated in amytrophic (sic) lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking.</strong>
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Hum. Molec. Genet. 23: 3579-3595, 2014. Note: Erratum: Hum. Molec. Genet. 26: 4093-4094, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24549040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24549040</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24549040[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=24549040" 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/ddu068" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
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<a id="Freibaum2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Freibaum, B. D., Lu, Y., Lopez-Gonzalez, R., Kim, N. C., Almeida, S., Lee, K.-H., Badders, N., Valentine, M., Miller, B. L., Wong, P. C., Petrucelli, L., Kim, H. J., Gao, F.-B., Taylor, J. P.
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<strong>GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport.</strong>
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Nature 525: 129-133, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26308899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26308899</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26308899[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=26308899" 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/nature14974" target="_blank">Full Text</a>]
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</p>
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<a id="14" class="mim-anchor"></a>
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<a id="Gomez-Tortosa2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Gomez-Tortosa, E., Gallego, J., Guerrero-Lopez, R., Marcos, A., Gil-Neciga, E., Sainz, M. J., Diaz, A., Franco-Macias, E., Trujillo-Tiebas, M. J., Ayuso, C., Perez-Perez, J.
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<strong>C9ORF72 hexanucleotide expansions of 20-22 repeats are associated with frontotemporal deterioration.</strong>
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Neurology 80: 366-370, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23284068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23284068</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23284068" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e31827f08ea" target="_blank">Full Text</a>]
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</p>
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<a id="15" class="mim-anchor"></a>
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<a id="Haeusler2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Haeusler, A. R., Donnelly, C. J., Periz, G., Simko, E. A. J., Shaw, P. G., Kim, M.-S., Maragakis, N. J., Troncoso, J. C., Pandey, A., Sattler, R., Rothstein, J. D., Wang, J.
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<strong>C9orf72 nucleotide repeat structures initiate molecular cascades of disease.</strong>
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[<a href="https://doi.org/10.1038/nature13124" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature23451" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.aaf1064" target="_blank">Full Text</a>]
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<a id="29" class="mim-anchor"></a>
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<a id="Sellier2016" class="mim-anchor"></a>
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<div class="">
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Sellier, C., Campanari, M.-L., Corbier, C. J., Gaucherot, A., Kolb-Cheynel, I., Oulad-Abdelghani, M., Ruffenach, F., Page, A., Ciura, S., Kabashi, E., Charlet-Berguerand, N.
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<strong>Loss of C9ORF72 impairs autophagy and synergizes with polyQ ataxin-2 to induce motor neuron dysfunction and cell death.</strong>
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EMBO J. 35: 1276-1297, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27103069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27103069</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27103069[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=27103069" 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/10.15252/embj.201593350" target="_blank">Full Text</a>]
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<a id="30" class="mim-anchor"></a>
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<a id="Shao2022" class="mim-anchor"></a>
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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.
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<strong>Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration.</strong>
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Science 378: 94-99, 2022.
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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.abq7860" target="_blank">Full Text</a>]
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<a id="31" class="mim-anchor"></a>
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<a id="Smith2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Smith, B. N., Newhouse, S., Shatunov, A., Vance, C., Topp, S., Johnson, L., Miller, J., Lee, Y., Troakes, C., Scott, K. M., Jones, A., Gray, I., and 34 others.
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<strong>The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder.</strong>
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Europ. J. Hum. Genet. 21: 102-108, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22692064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22692064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22692064[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=22692064" 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/ejhg.2012.98" target="_blank">Full Text</a>]
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<a id="32" class="mim-anchor"></a>
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<a id="Su2020" class="mim-anchor"></a>
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Su, M.-Y., Fromm, S. A., Zoncu, R., Hurley, J. H.
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<strong>Structure of the C9orf72 ARF GAP complex that is haploinsufficient in ALS and FTD.</strong>
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Nature 585: 251-255, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32848248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32848248</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32848248[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=32848248" 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/s41586-020-2633-x" target="_blank">Full Text</a>]
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<a id="33" class="mim-anchor"></a>
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<a id="Sullivan2016" class="mim-anchor"></a>
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Sullivan, P. M., Zhou, X., Robins, A. M., Paushter, D. H., Kim, D., Smolka, M. B., Hu, F.
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<strong>The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway.</strong>
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Acta Neuropath. Commun. 4: 51, 2016. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27193190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27193190</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27193190[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=27193190" 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/10.1186/s40478-016-0324-5" target="_blank">Full Text</a>]
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<a id="van der Zee2013" class="mim-anchor"></a>
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van der Zee, J., Gijselinck, I., Dillen, L., Van Langenhove, T., Theuns, J., Engelborghs, S., Philtjens, S., Vandenbulcke, M., Sleegers, K., Sieben, A., Baumer, V., Maes, G., and 50 others.
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<strong>A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats.</strong>
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Hum. Mutat. 34: 363-373, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23111906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23111906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23111906[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=23111906" 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/humu.22244" target="_blank">Full Text</a>]
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<a id="35" class="mim-anchor"></a>
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<a id="Xi2013" class="mim-anchor"></a>
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Xi, Z., Zinman, L., Moreno, D., Schymick, J., Liang, Y., Sato, C., Zheng, Y., Ghani, M., Dib, S., Keith, J., Robertson, J., Rogaeva, E.
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<strong>Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion.</strong>
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Am. J. Hum. Genet. 92: 981-989, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23731538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23731538</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23731538[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=23731538" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2013.04.017" target="_blank">Full Text</a>]
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<a id="36" class="mim-anchor"></a>
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<a id="Yang2016" class="mim-anchor"></a>
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Yang, M., Liang, C., Swaminathan, K., Herrlinger, S., Lai, F., Shiekhattar, R., Chen, J.-F.
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<strong>A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy.</strong>
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Sci. Adv. 2: e1601167, 2016. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27617292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27617292</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27617292[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=27617292" 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/sciadv.1601167" target="_blank">Full Text</a>]
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<a id="37" class="mim-anchor"></a>
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<a id="Zhang2015" class="mim-anchor"></a>
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Zhang, K., Donnelly, C. J., Haeusler, A. R., Grima, J. C., Machamer, J. B., Steinwald, P., Daley, E. L., Miller, S. J., Cunningham, K. M., Vidensky, S., Gupta, S., Thomas, M. A., and 9 others.
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<strong>The C9orf72 repeat expansion disrupts nucleocytoplasmic transport.</strong>
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Nature 525: 56-61, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26308891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26308891</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26308891[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=26308891" 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/nature14973" target="_blank">Full Text</a>]
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<a id="Zhang2019" class="mim-anchor"></a>
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Zhang, Y.-J., Guo, L., Gonzales, P. K., Gendron, T. F., Wu, Y., Jansen-West, K., O'Raw, A. D., Pickles, S. R., Prudencio, M., Carlomagno, Y., Gachechiladze, M. A., Ludwig, C., and 23 others.
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<strong>Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity.</strong>
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Science 363: eaav2606, 2019. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30765536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30765536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30765536[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=30765536" 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.aav2606" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 11/28/2022
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Bao Lige - updated : 02/01/2022<br>Bao Lige - updated : 12/09/2021<br>Ada Hamosh - updated : 03/02/2021<br>Ada Hamosh - updated : 12/11/2020<br>Ada Hamosh - updated : 09/04/2020<br>Ada Hamosh - updated : 10/16/2019<br>Bao Lige - updated : 07/30/2018<br>Paul J. Converse - updated : 10/10/2017<br>Patricia A. Hartz - updated : 08/30/2017<br>Patricia A. Hartz - updated : 06/01/2017<br>Ada Hamosh - updated : 09/12/2016<br>Patricia A. Hartz - updated : 09/07/2016<br>Paul J. Converse - updated : 09/01/2016<br>Ada Hamosh - updated : 2/22/2016<br>Ada Hamosh - updated : 6/29/2015<br>Ada Hamosh - updated : 9/30/2014<br>Cassandra L. Kniffin - updated : 8/18/2014<br>Ada Hamosh - updated : 4/17/2014<br>Cassandra L. Kniffin - updated : 1/8/2014<br>Cassandra L. Kniffin - updated : 11/14/2013<br>Cassandra L. Kniffin - updated : 6/27/2013<br>Cassandra L. Kniffin - updated : 4/22/2013<br>Cassandra L. Kniffin - updated : 3/28/2013<br>Cassandra L. Kniffin - updated : 3/20/2013<br>Cassandra L. Kniffin - updated : 10/3/2011
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Patricia A. Hartz : 9/30/2011
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carol : 11/29/2022
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alopez : 11/28/2022<br>mgross : 02/01/2022<br>mgross : 12/09/2021<br>mgross : 03/02/2021<br>alopez : 12/11/2020<br>alopez : 09/04/2020<br>alopez : 10/31/2019<br>alopez : 10/16/2019<br>carol : 09/20/2018<br>carol : 07/30/2018<br>mgross : 12/05/2017<br>mgross : 10/10/2017<br>mgross : 08/30/2017<br>alopez : 06/01/2017<br>carol : 05/09/2017<br>alopez : 09/12/2016<br>alopez : 09/07/2016<br>mgross : 09/01/2016<br>alopez : 02/22/2016<br>alopez : 2/22/2016<br>alopez : 2/22/2016<br>alopez : 6/29/2015<br>alopez : 9/30/2014<br>alopez : 8/20/2014<br>mcolton : 8/19/2014<br>ckniffin : 8/18/2014<br>carol : 7/29/2014<br>alopez : 4/17/2014<br>carol : 1/17/2014<br>ckniffin : 1/8/2014<br>alopez : 11/18/2013<br>ckniffin : 11/14/2013<br>alopez : 7/9/2013<br>tpirozzi : 7/3/2013<br>tpirozzi : 7/3/2013<br>tpirozzi : 7/3/2013<br>ckniffin : 6/27/2013<br>carol : 4/23/2013<br>ckniffin : 4/22/2013<br>carol : 4/1/2013<br>ckniffin : 3/28/2013<br>carol : 3/27/2013<br>ckniffin : 3/20/2013<br>terry : 7/5/2012<br>alopez : 10/27/2011<br>carol : 10/4/2011<br>carol : 10/4/2011<br>ckniffin : 10/3/2011<br>mgross : 9/30/2011
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<span class="mim-font">
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<strong>*</strong> 614260
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<h3>
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CHROMOSOME 9 OPEN READING FRAME 72; C9ORF72
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: C9orf72</em></strong>
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<strong>
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<em>
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Cytogenetic location: 9p21.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 9:27,546,546-27,573,866 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<th>
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Location
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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9p21.2
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</span>
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</td>
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<td>
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<span class="mim-font">
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Frontotemporal dementia and/or amyotrophic lateral sclerosis 1
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</td>
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<span class="mim-font">
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105550
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</span>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<strong>Cloning and Expression</strong>
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</h4>
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</div>
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<p>DeJesus-Hernandez et al. (2011) characterized 3 C9ORF72 transcripts. Variants 1 and 3 contain different noncoding first exons (exons 1b and 1a, respectively) fused to coding exons 2 through 11. Both variants encode the same deduced 481-amino acid protein. Variant 2 contains exon 1a fused to coding exons 2 through 5 and encodes a deduced 222-amino acid protein. Exon 1a in variant 2 uses a different 3-prime donor site than that used by exon 1a in variant 3. RT-PCR analysis with variant-specific primers detected expression of variants 1 and 3 in all tissues examined. Variant 2 was highly expressed in testis, fetal brain, cerebellum, and frontal cortex, with lower expression in kidney, lung, and hippocampus, and no expression in liver and lymphoblasts. Western blot analysis revealed C9ORF72 proteins with apparent molecular masses of 55 and 25 kD in human lymphoblasts. Immunohistochemical analysis of brain showed that C9ORF72 was largely a neuronal cytoplasmic protein. It also seemed to localize at large presynaptic terminals. </p><p>Independently, Renton et al. (2011) reported C9ORF72 isoforms containing 221 and 481 amino acids. Expression array analysis detected C9ORF72 expression in all brain regions examined and spinal cord, with highest expression in cerebellum. Immunohistochemical analysis showed nuclear expression of C9ORF72 in a normal human fibroblast cell line and a mouse motor neuron cell line. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>DeJesus-Hernandez et al. (2011) determined that the C9ORF72 gene contains 12 exons, including 2 alternate noncoding first exons (exons 1a and 1b). </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>DeJesus-Hernandez et al. (2011) and Renton et al. (2011) reported that the C9ORF72 gene maps to chromosome 9p21. </p>
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</span>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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Su et al. (2020) determined the structure of the C9ORF72-SMCR8 (617074)-WDR41 (617502) complex by cryoelectron microscopy. C9ORF72 and SMCR8 both contain longin and DENN (differentially expressed in normal and neoplastic cells) domains, and WDR41 is a beta-propeller protein that binds to SMCR8 such that the whole structure resembles an eye-slip hook. Contacts between WDR41 and the DENN domain of SMCR8 drive the lysosomal localization of the complex in conditions of amino acid starvation. The structure suggested that C9ORF72-SMCR8 is a GTPase-activating protein (GAP), and Su et al. (2020) found that C9ORF72-SMCR8-WDR41 acts as a GAP for the ARF family of small GTPases. Su et al. (2020) concluded that their data data shed light on the function of C9ORF72 in normal physiology, and in amyotrophic lateral sclerosis and frontotemporal degeneration. </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>Gene Function</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Haeusler et al. (2014) identified a molecular mechanism by which structural polymorphism of the C9ORF72 hexanucleotide repeat expansion (HRE) leads to ALS/FTD (105550) pathology and defects. The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA/DNA hybrids (R-loops). The structural polymorphism causes a repeat length-dependent accumulation of transcripts aborted in the HRE region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin (164035) preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. Haeusler et al. (2014) concluded that distinct C9ORF72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases. </p><p>Farg et al. (2014) provided evidence that C9ORF72 plays a role in endosomal trafficking. Immunofluorescence studies indicated that C9ORF72 was expressed within vesicles in the nucleus and cytoplasm of human and mouse neuronal cell lines. C9ORF72 colocalized with several Rab proteins implicated in autophagy and endosomal transport, including RAB1 (179508), RAB7 (602298), and RAB11A (605570), in neuronal cells, mouse cortical neurons, and human spinal cord. C9ORF72 also localized with the autophagocytic marker LC3 (MAP1LC3A; 601242). Depletion of C9ORF72 using siRNA resulted in impaired endocytosis and impaired autophagy-mediated trafficking. Immunoprecipitation studies showed that C9ORF72 interacted with additional proteins involved in cellular trafficking pathways, such as ubiquilin-2 (UBQLN2; 300264), HNRNPA1 (164017), and HNRNPA2B1 (600124). Cellular overexpression of C9ORF72 interfered with proteasomal function and induced the formation of C9ORF72 aggregates and cytoplasmic stress bodies. Farg et al. (2014) suggested that C9ORF72 functions as a Rab guanine nucleotide exchange factor (Rab GEF) that regulates intracellular trafficking. </p><p>Both the sense and antisense transcripts of the GGGGCC repeats associated with C9ORF72 can be translated in an ATG-independent manner (without an ATG start codon) known as repeat-associated non-ATG (RAN) translation (Mori et al., 2013). The translation products of the sense and antisense transcripts of the expansion repeats associated with the C9ORF72 gene altered in neurodegenerative disease encode glycine:arginine (GR(n)) and proline:arginine (PR(n)) repeat polypeptides, respectively. Kwon et al. (2014) found that both peptides bound to hnRNPA2 (see 600124) hydrogels. When applied to cultured cells, both GR(20) and PR(20) peptides entered cells, migrated to the nucleus, bound nucleoli, and poisoned RNA biogenesis, which caused cell death. </p><p>Mizielinska et al. (2014) developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats, but not stop codon-interrupted 'RNA-only' repeats, in Drosophila caused adult-onset neurodegeneration. Thus, expanded repeats promoted neurodegeneration through dipeptide repeat proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence revealed that both poly-(glycine-arginine; GR) and poly-(proline-arginine; PR) proteins caused neurodegeneration. Mizielinska et al. (2014) concluded that their findings were consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9ORF72-mediated neurodegeneration. </p><p>To discover RNA-binding proteins that genetically modify GGGGCC (G4C2)-mediated neurogenesis, Zhang et al. (2015) performed a candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats. They identified RanGAP (the Drosophila ortholog of human RanGAP1, 602362), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppressed neurodegeneration. RanGAP physically interacted with HRE RNA and was mislocalized in HRE-expressing flies, neurons from C9ORF72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9ORF72 ALS patient brain tissue. Nuclear import was impaired as a result of HRE expression in the fly model and in C9ORF72 iPSC-derived neurons, and these deficits were rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Zhang et al. (2015) suggested that nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention. </p><p>Freibaum et al. (2015) independently generated transgenic flies expressing 8, 28, or 58 G4C2 repeat-containing transcripts that did not have a translation start site but contained an open reading frame for green fluorescent protein to detect repeat-associated non-AUG (RAN) translation. Freibaum et al. (2015) showed that these transgenic animals display dosage-dependent, repeat length-dependent degeneration in neuronal tissues and RAN translation of dipeptide repeat proteins, as observed in patients with C9ORF72-related disease. This model was used in a large-scale, unbiased genetic screen, ultimately leading to the identification of 18 genetic modifiers that encode components of the nuclear pore complex (NPC), as well as the machinery that coordinates the export of nuclear RNA and the import of nuclear proteins. Consistent with these results, Freibaum et al. (2015) found morphologic abnormalities in the architecture of the nuclear envelope in cells expressing expanded G4C2 repeats in vitro and in vivo. Moreover, the authors identified a substantial defect in RNA export resulting in retention of RNA in the nuclei of Drosophila cells expressing expanded G4C2 repeats and also in mammalian cells, including aged induced pluripotent stem cell-derived neurons from patients with C9ORF72-related disease. Freibaum et al. (2015) concluded that their studies showed that a primary consequence of G4C2 repeat expansion is the compromise of nucleocytoplasmic transport through the nuclear pore, revealing a novel mechanism of neurodegeneration. </p><p>Using mass spectrometric analysis, Sellier et al. (2016) identified several proteins that purified with epitope-tagged human C9ORF72 following transfection of mouse N2A cells, including Rab8a (165040), Rab39b (300774), Smcr8 (617074), Wdr41 (617502), p62 (SQSTM1; 601530), Hsc70 (HSPA8; 600816), Hsp90 (see 140571), and Bag3 (603883). Coimmunoprecipitation analysis of human constructs confirmed direct interaction between the long, but not short, isoform of C9ORF72 with SMCR8 and WDR41. The 3 proteins functioned as a GDP-GTP exchange factor for RAB8A and RAB39B, which are small GTPases involved in vesicle trafficking and autophagy. Knockdown of C9orf72, Smcr8, or Wdr41 in cultured mouse cortical neurons inhibited autophagy and led to accumulation of cytoplasmic aggregates of p62 and Tdp43 (TARDBP; 605078), and failure to lipidate Lc3b (MAP1LC3B; 609604), which is required for formation of autophagic vesicles. Knockdown of C9orf72 also potentiated aggregation and neurotoxicity of ataxin-2 (ATXN2; 601517) with intermediate length of polyglutamine expansion (Q30x), but did not induce aggregation and toxicity in wildtype ataxin-2. Sellier et al. (2016) concluded that C9ORF72, SMCR8, and WDR41 interact in a complex that regulates autophagy and clears deleterious protein aggregates. </p><p>Using a proteomic screen followed by coimmunoprecipitation analysis, Sullivan et al. (2016) independently found that the long isoform of C9ORF72 interacted with SMCR8. The C9ORF72-SMCR8 heterodimer also interacted with the Golgi complex membrane protein WDR41. Furthermore, the C9ORF72-SMCR8-WDR41 trimer associated with the FIP200 (RB1CC1; 606837)-ULK1 (603168)-ATG13 (615088)-ATG10 (610800) complex, which is essential for autophagy initiation. </p><p>Using genome-editing strategies with human cells, Amick et al. (2016) found that C9ORF72 robustly interacted with SMCR8. C9ORF72 localized to lysosomes, and this localization was negatively regulated by amino acid availability. Studies of knockout cells revealed phenotypes that supported a role for C9ORF72 at lysosomes, including lysosomes swelling in the absence of C9ORF72 and impaired responses of mTORC1 (601231) signaling to changes in amino acid availability due to depletion of C9ORF72 or SMCR8. Amick et al. (2016) concluded that C9ORF72 and SMCR8 have strong physical and functional interactions at lysosomes. </p><p>Using proteomic and immunoprecipitation analyses, Ciura et al. (2016) found that C9ORF72 existed in a complex with SMCR8 and WDR41. The complex acted as GDP/GTP exchange factor for RAB8 and RAB39, which are involved in autophagy. C9ORF72 depletion in neuronal cell cultures led to accumulation of unresolved aggregates of SQSTM1 and phosphorylated TARDBP, but it did not result in major neuronal toxicity. Coexpression of intermediate polyglutamine repeats (30Q) within ATXN2 combined with C9ORF72 depletion increased aggregation of ATXN2 and neuronal toxicity. Ciura et al. (2016) concluded that C9ORF72 plays an important role in the autophagy pathway and interacts genetically with ATXN2. </p><p>Using HEK293 cells, Yang et al. (2016) observed interaction of C9ORF72 with SMCR8, WDR41, and ATG101 (615089) and found that this complex associated with the ULK1 complex. The C9ORF72 complex exhibited GTPase activity and acted as a guanine nucleotide exchange factor for RAB39B. In mouse neuroblastoma cells, interaction of C9orf72 with Smcr8 depended on the DENN domains of each protein. Mouse cells deficient in Smcr8 had a reduced capacity to induce autophagy. Autophagy induction was compromised by knockdown of C9orf72 and was also disrupted in cells lacking both C9orf72 and Smcr8. In HEK293 cells, the C9ORF72/SMCR8 complex interacted with the ULK1/ATG13 complex, and this interaction was facilitated by amino acid starvation. Expression of Ulk1 was enhanced in mouse cells lacking Smcr8, but not in cells lacking C9orf72. Moreover, autophagic flux was defective in Smcr8-deficient cells, but it was increased by knockdown of C9orf72. Yang et al. (2016) concluded that C9ORF72 and SMCR8 have roles in modulating autophagy induction by regulating ULK1, but that they play distinct roles in regulating autophagic flux. </p><p>Kramer et al. (2016) found that targeting Spt4 selectively decreased production of both sense and antisense expanded transcripts of C9orf72, as well as their translated dipeptide repeat (DPR) products, and also mitigated degeneration in animal models. Knockdown of SUPT4H1 (603555), the human Spt4 ortholog, similarly decreased production of sense and antisense RNA foci and DPR proteins in patient cells. The authors argued that single-factor targeting has advantages over targeting sense and antisense repeats separately. </p><p>Chang et al. (2016) found that a synthetic glycine-alanine (GA) DPR from C9ORF72 with 15 repeats , referred to as (GA)15, rapidly formed amyloid fibrils, starting with formation of short filaments and, later, ribbon-type fibrils. (GA)15 aggregates were neurotoxic and exhibited cell-to-cell transmission properties in which the aggregates could be taken from the extracellular space and transmitted among human neuroblastoma cells. </p><p>By proteomic analysis, Lee et al. (2016) showed that DPR species containing arginine (GR and PR) produced from hexanucleotide repeat expansion in C9ORF72 shared a common set of interactors enriched in low complexity sequence domains (LCDs) in HEK293T cells. Most GR and PR interactors were components of membraneless organelles, with some overlap between interactors of GR/PR and those identified in flies expressing an expanded G4C2 repeat. Toxicity test revealed that these arginine-containing DPRs were particularly toxic in Drosophila and mammalian cells. In vitro and live-cell analyses with HeLa cells showed that GR and PR DPRs localized to nucleolar substructures and impaired biophysical properties of NPM1 (164040), thereby disrupting nucleolar dynamics and impairing nucleolar function. In living cells, GR and PR DPRs interacted with stress granule proteins and altered stress granule dynamics by promoting spontaneous assembly of poorly dynamic stress granules. GR and PR also inhibited cellular translation by directly interacting with LCD-containing RNA-binding proteins and altering their biophysical properties. Arginine-containing DPRs also impaired the assembly or dynamics of other membraneless organelles, such as nuclear speckles and Cajal bodies, in living cells. </p><p>Joung et al. (2017) found that activation of the long noncoding RNA EMICERI (617651) resulted in dose-dependent activation of its neighboring genes, including EQTN (617653), MOB3B (617652), IFNK (615326), and CORF72. </p><p>Kramer et al. (2018) noted that C9ORF72 DPR proteins induce an endoplasmic reticulum (ER) stress response. Using genomewide CRISPR-Cas9 knockout screens in the human cell line K562, followed by secondary CRISPR-Cas9 screens in primary mouse neurons, Kramer et al. (2018) uncovered modifiers of C9ORF72 DPR toxicity, including Tmx2 (616715), an ER-resident transmembrane thioredoxin protein. Tmx2 was found to modulate the C9ORF72 DPR-induced ER-stress response in neurons and to improve the survival of human-induced motor neuronal cells from C9ORF72 ALS patients. </p><p>Using genomewide knockout screens in human cells, Cheng et al. (2019) showed that the NXF1 (602647)-NXT1 (605811) pathway mediated nuclear export of C9ORF72 GGGGCC repeat-containing RNA to the cytoplasm for translation, thereby influencing C9ORF72 DPR protein production. The RNA helicase DDX3X (300160) was identified as a modifier of DPR protein production, as it suppressed RAN translation of C9ORF72 (GGGGCC)n repeats by directly and selectively binding to GGGGCC repeat RNA. Binding to GGGGCC repeat RNA activated DDX3X ATPase activity for RNA structure unwinding, and translation repression required DDX3X helicase activity. Similarly, loss of Bel, the Drosophila ortholog of DDX3X, enhanced GGGGCC repeat toxicity in Drosophila, whereas ectopic expression of Bel partially rescued it, identifying Bel as a genetic modifier of GGGGCC repeat-mediated toxicity in vivo. ELISA revealed that DDX3X expression modulated repeat-mediated toxicity in ALS patient cells by regulating DPR production from RAN translation </p><p>Ortega et al. (2020) found that the hexanucleotide repeat expansion in C9ORF72 (614260.0001) associated with autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis (FTDALS1; 105550) led to proteome-wide nucleocytoplasmic redistribution, with more proteins accumulating in cytoplasm. Analysis with a Drosophila disease model identified Erf1 (ETF1; 600285) as a genetic interactor of mutant C9orf72 toxicity, and ERF1 was among the proteins that exhibited a significant magnitude of change in localization in association with the C9ORF72 repeat expansion. Analysis with motor neurons derived from pluripotent stem cells confirmed that ERF1 was redistributed in motor neurons and postmortem tissue of ALS patients with a C9ORF72 repeat expansion. Redistribution of ERF1 resulted in a functional shift of EFR1 from protein translation to nonsense-mediated decay (NMD) of mRNA molecules. This functional shift of EFR1 targeted C9ORF72 mRNA and induced UPF1 (601430)-dependent degradation of the expanded C9ORF72 transcript, thereby conferring a protective effect against toxicity of the C9ORF72 repeat expansion. </p><p>Zhang et al. (2019) developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded C9ORF72 GGGGCC (G4C2) repeats. The expression of green fluorescent protein-conjugated (PR)50 (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. Zhang et al. (2019) found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1a (HP1a; 604478) liquid-phase disruptions, decreases in HP1a expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1a, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Zhang et al. (2019) concluded that they uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of C9ORF72-associated FTD and ALS. </p><p>McCauley et al. (2020) found that blood-derived macrophages, whole blood, and brain tissue from patients with FTDALS1 exhibited an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD. Moreover, this increased interferon response could be suppressed with an inhibitor of STING (612374), a key regulator of the innate immune response to cytosolic DNA. McCauley et al. (2020) concluded that these findings, as well as their findings in C9orf72 mutant mice (see ANIMAL MODEL), suggested that patients with FTDALS1 have an altered immunophenotype because reduced levels of C9ORF72 cannot suppress inflammation mediated by induction of type I interferons by STING. </p><p>Shao et al. (2022) studied the interplay of the FTD-ALS-associated genes C9ORF72, TBK1 (604834), and TDP43 (605078). 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>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In affected members of large families with autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis mapping to chromosome 9p21 (FTDALS1; 105550), DeJesus-Hernandez et al. (2011) and Renton et al. (2011) simultaneously and independently identified a heterozygous expanded hexanucleotide repeat (GGGGCC) located between the noncoding exons 1a and 1b of the C9ORF72 gene (614260.0001). The maximum size of the repeat in healthy controls was 23 units, whereas it was expanded to 700 to 1,600 (DeJesus-Hernandez et al., 2011) or 250 repeats (Renton et al., 2011) in patients. DeJesus-Hernandez et al. (2011) identified this expanded hexanucleotide repeat in 16 (61.5%) of a series of 26 families with the disorder, as well as in 11.7% of familial FTD and 23.5% of familial ALS from 3 patient series. Sporadic cases with the expansion were also identified. Overall, 75 (10.4%) of 722 unrelated patients with FTD, ALS, or both were found to carry an expanded GGGGCC repeat. Renton et al. (2011) found the expanded repeat in 46.4% of Finnish familial ALS cases and in 21% of sporadic cases from Finland, as well as in 38.1% of 268 familial ALS probands of European origin. Both DeJesus-Hernandez et al. (2011) and Renton et al. (2011) concluded that it is the most common genetic abnormality in FTD/ALS. The expanded repeat is located in the promoter region of C9ORF72 transcript variant 1 and in intron 1 of transcript variants 2 and 3. In the study of DeJesus-Hernandez et al. (2011), transcript-specific cDNA amplified from frozen frontal cortex brain tissue from an affected individual showed absence of the variant 1 transcribed from the mutant RNA, whereas transcription of variants 2 and 3 was normal. mRNA expression analysis of variant 1 was decreased to about 50% in lymphoblast cells from a patient and in frontal cortex samples from other patients. These findings were consistent with a loss-of-function mechanism. However, protein levels of these variants were similar to controls, and analysis of patient frontal cortex and spinal cord tissue showed that the transcribed expanded GGGGCC repeat formed nuclear RNA foci, suggesting a gain-of-function mechanism. </p><p>Using repeat-primed PCR, Beck et al. (2013) identified 96 repeat-primed PCR expansions in a large population- and patient-based cohort: there were 85 (2.9%) expansions among 2,974 patients with various neurodegenerative diseases and 11 (0.15%) expansions among 7,579 controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in patients was 800 to 4,400. Large expansions were also detected in the population controls. There were some differences in expansion size and morphology between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, supported multiple expansion events on the same haplotype background. The findings suggested that there may be a higher prevalence of expanded C9ORF72 repeat carriers than previously thought. </p><p>Using 2 methods, Xi et al. (2013) investigated the CpG methylation profile of genomic DNA from the blood of individuals with ALS, including 37 G4C2 expansion carriers and 64 noncarriers, 76 normal controls, and family members of 7 ALS patients with the expansion. Hypermethylation of the CpG island 5-prime to the G4C2 repeat was associated with presence of the expansion (p less than 0.0001). A higher degree of methylation was significantly correlated with a shorter disease duration (p less than 0.01), associated with familial ALS (p = 0.009) and segregated with the expansion in 7 investigated families. Methylation changes were not detected in either normal or intermediate alleles (up to 43 repeats), raising the question of whether the cutoff of 30 repeats for pathologic alleles was adequate. The findings suggested that pathogenic repeat expansion of the G4C2 allele in C9ORF72 may lead to epigenetic changes, such as gene expression silencing, that may be associated with disease. </p>
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<strong>Animal Model</strong>
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<p>Ciura et al. (2013) found expression of the C9orf72 gene in the brain and spinal cord of zebrafish embryos. Morpholino knockdown of C9orf72 in zebrafish resulted in disrupted neuronal arborization and shortening of the motor neuron axons compared to controls, as well as motor deficits. These deficits were rescued upon overexpression of human C9orf72 mRNA transcripts. These results revealed a pathogenic consequence of decreased C9orf72 levels, supporting a loss of function mechanism of disease. </p><p>Chew et al. (2015) developed a mouse model to mimic both neuropathologic and clinical FTD/ALS phenotypes caused by mutations in the C9ORF72 gene. The authors expressed 66 G4C2 repeats (G4C2(66)) throughout the murine CNS via somatic brain transgenesis mediated by adeno-associated virus. The brains of 6-month-old mice contained nuclear RNA foci, inclusions of poly(Gly-Pro), poly(Gly-Ala), and poly(Gly-Arg) dipeptide repeat proteins, as well as TDP43 (605078) pathology. These mouse brains also exhibited cortical neuron and cerebellar Purkinje cell loss, astrogliosis, and decreased weight. The G4C2(66) mice also developed behavioral abnormalities similar to clinical symptoms of FTD/ALS caused by C9ORF72 mutations, including hyperactivity, anxiety, antisocial behavior, and motor deficits. </p><p>O'Rourke et al. (2016) found that 2 independent mouse lines lacking the C9orf72 ortholog in all tissues developed normally and aged without motor neuron disease. However, C90rf72 -/- mice developed progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells. Loss of C9orf72 led to lysosomal accumulation and altered immune responses in macrophages and microglia, with age-related neuroinflammation resembling C9ORF72-related ALS but not sporadic ALS human tissue. O'Rourke et al. (2016) concluded that C9ORF72 is required for normal myeloid cell function and proposed that altered microglial function may contribute to neurodegeneration in C9ORF72 expansion carriers. </p><p>Using CRISPR/Cas9 gene editing system, Sullivan et al. (2016) created C9orf72 -/- mice, which showed no apparent growth defect, but had obvious lymph node and spleen enlargement that became more severe with age. Livers of C9orf72 -/- mice also showed some enlargement, but brains appeared normal. Western blot and immunohistochemical analysis of C9orf72 -/- lymph node, spleen, and liver showed increased content of factors involved in the autophagy/lysosomal pathway. Sullivan et al. (2016) concluded that deficiency in C9orf72 causes a defect in autophagy, likely downstream of Ulk1 activation in autophagy initiation. </p><p>Using a zebrafish model, Ciura et al. (2016) showed that partial knockdown of C9orf72 combined with intermediate repeat expansion of Atxn2 caused locomotion deficits and abnormal axonal projections from spinal motor neurons. </p><p>Burberry et al. (2020) reported that an environment with reduced abundance of immune-stimulating bacteria protects C9orf72-mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathologic inflammatory response, Burberry et al. (2020) found that reducing the microbial burden in mutant mice with broad spectrum antibiotics, as well as transplanting gut microflora from a protective environment, attenuated inflammatory phenotypes, even after their onset. Burberry et al. (2020) concluded that their studies provided further evidence that the microbial composition of the gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system. </p><p>McCauley et al. (2020) found that myeloid cell-specific loss of C9orf72 in mice was sufficient to recapitulate the age-dependent lymphoid hypertrophy and autoinflammation observed in C9orf72-knockout mice. Dendritic cells from C9orf72-knockout mice showed marked early activation of type I interferon response, and C9orf72-null myeloid cells were selectively hyperresponsive to activators of Sting. C9orf72-null myeloid cells exhibited diminished degradation of Sting through the autolysosomal pathway, and blocking Sting suppressed hyperactive type I interferon responses in C9orf72-null immune cells, as well as splenomegaly and inflammation in C9orf72-knockout mice. Moreover, mice lacking 1 or both copies of C9orf72 were more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune disease seen in people with FTDALS1. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>1 Selected Example):</strong>
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<span class="mim-font">
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<strong>.0001 FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 1</strong>
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C9ORF72, (GGGGCC)n REPEAT EXPANSION
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ClinVar: RCV000024147
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<p>DeJesus-Hernandez et al. (2011) identified a polymorphic hexanucleotide repeat (GGGGCC) located between the noncoding exons 1a and 1b of the C9ORF72 gene. The maximum size of the repeat in healthy controls was 23 units, whereas it was expanded in members of a large family with frontotemporal dementia and/or amyotrophic lateral sclerosis mapping to chromosome 9p21 (FTDALS1; 105550) (Boxer et al., 2011). Affected individuals had expanded repeat units ranging from 700 to 1,600. Further analysis identified this expanded hexanucleotide repeat in 16 (61.5%) of a series of 26 families with the disorder, as well as in 11.7% of familial FTD and 23.5% of familial ALS from 3 patient series. Sporadic cases with the expansion were also identified. Overall, 75 (10.4%) of 722 unrelated patients with FTD, ALS, or both were found to carry an expanded GGGGCC repeat, and DeJesus-Hernandez et al. (2011) concluded that it is the most common genetic abnormality in FTD/ALS. Longer repeats were associated with the A allele at SNP rs3849942, which marked a disease haplotype. The expanded repeat is located in the promoter region of C9ORF72 transcript variant 1 and in intron 1 of transcript variants 2 and 3. Tissue from affected individuals showed reduced or absent mRNA levels of C9ORF72 variants 1 and 3 compared to nonrepeat carriers, consistent with a loss-of-function mechanism. However, protein levels of these variants were similar to controls, and analysis of patient frontal cortex and spinal cord tissue showed that the transcribed expanded GGGGCC repeat formed nuclear RNA foci, suggesting a gain-of-function mechanism. </p><p>Simultaneously and independently, Renton et al. (2011) identified the GGGGCC expanded repeat as a cause of FTD/ALS in families reported by Pearson et al. (2011) and Mok et al. (2012). The expanded repeat was also found in 46.4% of Finnish familial ALS cases and in 21% of sporadic cases. PCR assays showed that Finnish controls had between 0 and 22 repeats. FISH studies showed that the expansion in a family from Wales (Pearson et al., 2011) was at least 250 repeats. In addition, an expanded repeat was found in 102 (38.1%) of 268 familial ALS probands of European origin. Real-time RT-PCR analysis of expression in frontal cortex tissue from patients and controls did not detect conclusive changes in RNA levels and produced inconsistent results. Nevertheless, Renton et al. (2011) postulated that a disruption in RNA metabolism likely underlies this disorder. </p><p>Belzil et al. (2013) identified a hexanucleotide repeat expansion in the C9ORF72 gene in 13 (52%) of 25 patients of Caucasian origin with ALS who had a family history of cognitive impairment. </p><p>Van der Zee et al. (2013) assessed the distribution of C9ORF72 G4C2 expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort of 1,205 individuals ascertained by the European Early-Onset Dementia (EOD) consortium. A metaanalysis of the data and that of other European studies, including a total of 2,668 patients from 15 countries, showed that the frequency of C9ORF72 expansions in Western Europe was 9.98% in FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of 29.33% and 20.73%, respectively, consistent with the hypothesis of a Scandinavian founder effect. However, Spain also showed a high frequency of the expansion, at 25.49%. In contrast, the prevalence in Germany was low, at 4.82%. The phenotype was most often characterized by behavioral disturbances (95.7%). Postmortem examination of a small number of cases showed TDP43 (605078) and p62 (601530) deposits in the brain. Intermediate repeats (7 to 24 repeat units) were found to be strongly correlated with the risk haplotype tagged by a T allele of SNP rs2814707. In vitro reporter gene expression studies showed significantly decreased transcriptional activity of C9ORF72 with increasing number of normal repeat units, consistent with a loss of function. This was also observed with intermediate repeats, suggesting that they might act as predisposing alleles. There was also a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the expanded repeat in expansion carriers, suggesting that pathologic expansion may be due to replication slippage. </p><p>Smith et al. (2013) identified the expanded hexanucleotide repeat in C9ORF72 in 226 (17%) of 1,347 patients with ALS with or without FTD collected from 5 European populations in whom known ALS genes had been excluded. The expansion was also observed in 3 (0.3%) of 856 controls, yielding an odds ratio (OR) of 57 (p = 4.12 x 10(-47)), but also indicating incomplete penetrance. Haplotype analysis identified a common 82-SNP disease haplotype in the majority of 137 cases studied, indicating a single common founder in these European populations. The mutation was estimated to have arisen 6,300 years ago. The disease haplotype was found in almost 15% of European controls. The average number of pathogenic repeats on the disease haplotype was 8, with a spread of expanded alleles up to 26. The most prevalent number of repeats on other haplotypes was 2. The findings suggested that the background disease haplotype is intrinsically unstable, tending to generate longer repeats. The findings showed that the C9ORF72 expanded repeat is the most common genetic cause of ALS with or without FTD across Europe. </p><p>Mori et al. (2013) found that most of the characteristic intracellular inclusions in ALS or FTLD caused by the C9orf72 hexanucleotide repeat expansion contain poly-(gly-ala) and, to a lesser extent poly-(gly-pro), and poly-(gly-arg) dipeptide repeat proteins presumably generated by non-ATG-initiated translation from the expanded GGGGCC repeat in 3 reading frames. Mori et al. (2013) concluded that their findings directly linked the FTLD/ALS-associated genetic mutation to the predominant pathology in patients with C9orf72 hexanucleotide expansion. </p><p>Gomez-Tortosa et al. (2013) identified expanded C9ORF72 repeats in 9 (8.2%) of 109 Spanish probands with FTD. Four patients had more than 30 repeats, whereas 4 had 20 repeats and 1 had 22 repeats. None of the other 100 cases had greater than 13 repeats, and none of 216 controls had more than 14 repeats. In 4 families, the expanded 20- or 22-repeat alleles segregated consistently in all affected sibs, with the unaffected sibs having wildtype alleles (2-9 repeats). The 20- or 22-repeat allele was associated with the surrogate marker of the founder haplotype in all cases. Most of the 9 expansion carriers had extended periods with psychiatric symptoms and subjective cognitive complaints before clear neurologic deterioration, and there was no phenotypic difference between those with longer or shorter expansions. These findings suggested that short C9ORF72 hexanucleotide expansions in the 20- to 22-repeat range are also related to FTD. </p>
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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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<ol>
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<p class="mim-text-font">
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Amick, J., Roczniak-Ferguson, A., Ferguson, S. M.
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<strong>C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling.</strong>
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Molec. Biol. Cell 27: 3040-3051, 2016.
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Beck, J., Poulter, M., Hensman, D., Rohrer, J. D., Mahoney, C. J., Adamson, G., Campbell, T., Uphill, J., Borg, A., Fratta, P., Orrell, R. W., Malaspina, A., and 15 others.
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<strong>Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population.</strong>
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Am. J. Hum. Genet. 92: 345-353, 2013.
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Belzil, V. V., Daoud, H., Camu, W., Strong, M. J., Dion, P. A., Rouleau, G. A.
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<strong>Genetic analysis of SIGMAR1 as a cause of familial ALS with dementia.</strong>
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Boxer, A. L., Mackenzie, I. R., Boeve, B. F., Baker, M., Seeley, W. W., Crook, R., Feldman, H., Hsiung, G.-Y. R., Rutherford, N., Laluz, V., Whitwell, J., Foti, D., McDade, E., Molano, J., Karydas, A., Wojtas, A., Goldman, J., Mirsky, J., Sengdy, P., DeArmond, S., Miller, B. L., Rademakers, R.
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<strong>Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family.</strong>
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J. Neurol. Neurosurg. Psychiat. 82: 196-203, 2011.
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[Full Text: https://doi.org/10.1136/jnnp.2009.204081]
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Burberry, A., Wells, M. F., Limone, F., Couto, A., Smith, K. S., Keaney, J., Gillet, G., van Gastel, N., Wang, J.-Y., Pietilainen, O., Qian, M., Eggan, P., Cantrell, C., Mok, J., Kadiu, I., Scadden, DT., Eggan, K.
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<strong>C9orf72 suppresses systemic and neural inflammation induced by gut bacteria.</strong>
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Nature 582: 89-94, 2020.
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[PubMed: 32483373]
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Chang, Y.-J., Jeng, U-S., Chiang, Y.-L., Hwang, I.-S., Chen, Y.-R.
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<strong>The glycine-alanine dipeptide repeat from C9orf72 hexanucleotide expansions forms toxic amyloids possessing cell-to-cell transmission properties.</strong>
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J. Biol. Chem. 291: 4903-4911, 2016.
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[PubMed: 26769963]
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Cheng, W., Wang, S., Zhang, Z., Morgens, D. W., Hayes, L. R., Lee, S., Portz, B., Xie, Y., Nguyen, B. V., Haney, M. S., Yan, S., Dong, D., and 10 others.
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<strong>CRISPR-Cas9 screens identify the RNA helicase DDX3X as a repressor of C9ORF72 (GGGGCC)n repeat-associated non-AUG translation.</strong>
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Neuron 104: 885-898, 2019.
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[PubMed: 31587919]
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[Full Text: https://doi.org/10.1016/j.neuron.2019.09.003]
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Chew, J., Gendron, T. F., Prudencio, M., Sasaguri, H., Zhang, Y.-J., Castanedes-Casey, M., Lee, C. W., Jansen-West, K., Kurti, A., Murray, M. E., Bieniek, K. F., Bauer, P. O., and 15 others.
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<strong>C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits.</strong>
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Science 348: 1151-1154, 2015.
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[PubMed: 25977373]
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[Full Text: https://doi.org/10.1126/science.aaa9344]
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Ciura, S., Lattante, S., Le Ber, I., Latouche, M., Tostivint, H., Brice, A., Kabashi, E.
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<strong>Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis.</strong>
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Ann. Neurol. 74: 180-187, 2013.
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[PubMed: 23720273]
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[Full Text: https://doi.org/10.1002/ana.23946]
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<p class="mim-text-font">
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Ciura, S., Sellier, C., Campanari, M.-L., Charlet-Berguerand, N., Kabashi, E.
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<strong>The most prevalent genetic cause of ALS-FTD, C9orf72 synergizes the toxicity of ATXN2 intermediate polyglutamine repeats through the autophagy pathway.</strong>
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Autophagy 12: 1406-1408, 2016.
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[PubMed: 27245636]
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[Full Text: https://doi.org/10.1080/15548627.2016.1189070]
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<li>
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<p class="mim-text-font">
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DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., Kouri, N., Wojtas, A., and 16 others.
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<strong>Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.</strong>
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Neuron 72: 245-256, 2011.
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[PubMed: 21944778]
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[Full Text: https://doi.org/10.1016/j.neuron.2011.09.011]
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Farg, M. A., Sundaramoorthy, V., Sultana, J. M., Yang, S., Atkinson, R. A. K., Levina, V., Halloran, M. A., Gleeson, P. A., Blair, I. P., Soo, K. Y., King, A. E., Atkin, J. D.
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<strong>C9ORF72, implicated in amytrophic (sic) lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking.</strong>
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Hum. Molec. Genet. 23: 3579-3595, 2014. Note: Erratum: Hum. Molec. Genet. 26: 4093-4094, 2017.
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[PubMed: 24549040]
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[Full Text: https://doi.org/10.1093/hmg/ddu068]
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Freibaum, B. D., Lu, Y., Lopez-Gonzalez, R., Kim, N. C., Almeida, S., Lee, K.-H., Badders, N., Valentine, M., Miller, B. L., Wong, P. C., Petrucelli, L., Kim, H. J., Gao, F.-B., Taylor, J. P.
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<strong>GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport.</strong>
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Nature 525: 129-133, 2015.
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Ada Hamosh - updated : 11/28/2022<br>Bao Lige - updated : 02/01/2022<br>Bao Lige - updated : 12/09/2021<br>Ada Hamosh - updated : 03/02/2021<br>Ada Hamosh - updated : 12/11/2020<br>Ada Hamosh - updated : 09/04/2020<br>Ada Hamosh - updated : 10/16/2019<br>Bao Lige - updated : 07/30/2018<br>Paul J. Converse - updated : 10/10/2017<br>Patricia A. Hartz - updated : 08/30/2017<br>Patricia A. Hartz - updated : 06/01/2017<br>Ada Hamosh - updated : 09/12/2016<br>Patricia A. Hartz - updated : 09/07/2016<br>Paul J. Converse - updated : 09/01/2016<br>Ada Hamosh - updated : 2/22/2016<br>Ada Hamosh - updated : 6/29/2015<br>Ada Hamosh - updated : 9/30/2014<br>Cassandra L. Kniffin - updated : 8/18/2014<br>Ada Hamosh - updated : 4/17/2014<br>Cassandra L. Kniffin - updated : 1/8/2014<br>Cassandra L. Kniffin - updated : 11/14/2013<br>Cassandra L. Kniffin - updated : 6/27/2013<br>Cassandra L. Kniffin - updated : 4/22/2013<br>Cassandra L. Kniffin - updated : 3/28/2013<br>Cassandra L. Kniffin - updated : 3/20/2013<br>Cassandra L. Kniffin - updated : 10/3/2011
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carol : 11/29/2022<br>alopez : 11/28/2022<br>mgross : 02/01/2022<br>mgross : 12/09/2021<br>mgross : 03/02/2021<br>alopez : 12/11/2020<br>alopez : 09/04/2020<br>alopez : 10/31/2019<br>alopez : 10/16/2019<br>carol : 09/20/2018<br>carol : 07/30/2018<br>mgross : 12/05/2017<br>mgross : 10/10/2017<br>mgross : 08/30/2017<br>alopez : 06/01/2017<br>carol : 05/09/2017<br>alopez : 09/12/2016<br>alopez : 09/07/2016<br>mgross : 09/01/2016<br>alopez : 02/22/2016<br>alopez : 2/22/2016<br>alopez : 2/22/2016<br>alopez : 6/29/2015<br>alopez : 9/30/2014<br>alopez : 8/20/2014<br>mcolton : 8/19/2014<br>ckniffin : 8/18/2014<br>carol : 7/29/2014<br>alopez : 4/17/2014<br>carol : 1/17/2014<br>ckniffin : 1/8/2014<br>alopez : 11/18/2013<br>ckniffin : 11/14/2013<br>alopez : 7/9/2013<br>tpirozzi : 7/3/2013<br>tpirozzi : 7/3/2013<br>tpirozzi : 7/3/2013<br>ckniffin : 6/27/2013<br>carol : 4/23/2013<br>ckniffin : 4/22/2013<br>carol : 4/1/2013<br>ckniffin : 3/28/2013<br>carol : 3/27/2013<br>ckniffin : 3/20/2013<br>terry : 7/5/2012<br>alopez : 10/27/2011<br>carol : 10/4/2011<br>carol : 10/4/2011<br>ckniffin : 10/3/2011<br>mgross : 9/30/2011
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