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Entry
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- *606489 - EXOSOME COMPONENT 3; EXOSC3
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*606489</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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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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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</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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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/606489">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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<a href="#creationDate"><strong>Creation Date</strong></a>
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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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<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=ENSG00000107371;t=ENST00000327304" 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=51010" 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=606489" 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 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=ENSG00000107371;t=ENST00000327304" 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_001002269,NM_016042" 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_016042" 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=606489" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=16220&isoform_id=16220_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/EXOSC3" 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/4929673,7229638,8927588,12803247,14250820,14285758,50511939,50511943,119578668,158255164,158260165" 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/Q9NQT5" 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=51010" 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=ENSG00000107371;t=ENST00000327304" 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=EXOSC3" 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=EXOSC3" 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+51010" 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/EXOSC3" 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:51010" 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/51010" 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=ENST00000327304.10&hgg_start=37779714&hgg_end=37785092&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:17944" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/exosc3" 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=606489[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=606489[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/EXOSC3/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000107371" 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=EXOSC3" 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=EXOSC3" 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=EXOSC3" 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=EXOSC3&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/PA134926550" 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:17944" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0260648.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1913612" 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/EXOSC3#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:1913612" 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/51010/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=51010" 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=WBGene00010325;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-050706-140" 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:51010" 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=EXOSC3&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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606489
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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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EXOSOME COMPONENT 3; EXOSC3
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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RIBOSOMAL RNA-PROCESSING PROTEIN 40, S. CEREVISIAE, HOMOLOG OF; RRP40
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=EXOSC3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">EXOSC3</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/9/198?start=-3&limit=10&highlight=198">9p13.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:37779714-37785092&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'})">9:37,779,714-37,785,092</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/9/198?start=-3&limit=10&highlight=198">
|
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9p13.2
|
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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">
|
|
Pontocerebellar hypoplasia, type 1B
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/614678"> 614678 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</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">
|
|
<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>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/606489" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/606489" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</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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<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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<p>The EXOSC3 gene encodes a core component of the human RNA exosome complex that is present in the cytoplasm and the nucleus and especially enriched in the nucleolus (<a href="#1" class="mim-tip-reference" title="Brouwer, R., Allmang, C., Raijmakers, R., van Aarssen, Y., Egberts, W. V., Petfalski, E., van Venrooij, W. J., Tollervey, D., Pruijn, G. J. M. <strong>Three novel components of the human exosome.</strong> J. Biol. Chem. 276: 6177-6184, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11110791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11110791</a>] [<a href="https://doi.org/10.1074/jbc.M007603200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11110791">Brouwer et al., 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11110791" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Inherently unstable mammalian mRNAs contain AU-rich elements (AREs) within their 3-prime untranslated regions. In yeast, 3-prime-to-5-prime mRNA degradation is mediated by the exosome, a multisubunit particle. <a href="#2" class="mim-tip-reference" title="Chen, C.-Y., Gherzi, R., Ong, S.-E., Chan, E. L., Raijmakers, R., Pruijn, G. J. M., Stoecklin, G., Moroni, C., Mann, M., Karin, M. <strong>AU binding proteins recruit the exosome to degrade ARE-containing mRNAs.</strong> Cell 107: 451-464, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11719186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11719186</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00578-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11719186">Chen et al. (2001)</a> purified and characterized the human exosome by mass spectrometry and found its composition to be similar to its yeast counterpart. They identified the following protein subunits within the human exosome: p7, which is homologous to the yeast Rrp4 protein (<a href="/entry/602238">602238</a>); p8, which is homologous to the yeast Rrp42 protein (<a href="/entry/606488">606488</a>); p9, which is homologous to the yeast Rrp43 protein (OIP2; <a href="/entry/606019">606019</a>); p10, which is homologous to the yeast Rrp40 protein; p11, which is homologous to the yeast Mtr3 protein (<a href="/entry/606490">606490</a>); p12A, which is homologous to the yeast Rrp41 protein (<a href="/entry/606491">606491</a>); p12B, which is homologous to the yeast Rrp46 protein (<a href="/entry/606492">606492</a>); and p13, which is homologous to the yeast Csl4 protein (<a href="/entry/606493">606493</a>). They also identified 2 exosome-associated factors, p1 (<a href="/entry/600478">600478</a>) and p14 (MPP6; <a href="/entry/605500">605500</a>), that were not homologous to any yeast exosome components. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11719186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 searching an EST database for homologs of yeast exosome components, followed by PCR on a teratocarcinoma cell line and 5-prime RACE using placenta RNA, <a href="#1" class="mim-tip-reference" title="Brouwer, R., Allmang, C., Raijmakers, R., van Aarssen, Y., Egberts, W. V., Petfalski, E., van Venrooij, W. J., Tollervey, D., Pruijn, G. J. M. <strong>Three novel components of the human exosome.</strong> J. Biol. Chem. 276: 6177-6184, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11110791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11110791</a>] [<a href="https://doi.org/10.1074/jbc.M007603200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11110791">Brouwer et al. (2001)</a> isolated cDNAs encoding RRP40, RRP41, and RRP46. The deduced 275-amino acid RRP40 protein is 88% and 30% identical to the mouse and yeast sequences, respectively. Western blot analysis and immunofluorescence microscopy showed expression of a 31-kD protein in the nucleus, with additional forms expressed in the cytoplasm and the highest concentration in nucleolus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11110791" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>There are multiple alternatively spliced forms of EXOSC3, with the longest reading frame encoding a 275-residue protein (summary by <a href="#7" class="mim-tip-reference" title="Wan, J., Yourshaw, M., Mamsa, H., Rudnik-Schoneborn, S., Menezes, M. P., Hong, J. E., Leong, D. W., Senderek, J., Salman, M. S., Chitayat, D., Seeman, P., von Moers, A., and 14 others. <strong>Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.</strong> Nature Genet. 44: 704-708, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22544365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22544365</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22544365[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22544365">Wan et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22544365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#7" class="mim-tip-reference" title="Wan, J., Yourshaw, M., Mamsa, H., Rudnik-Schoneborn, S., Menezes, M. P., Hong, J. E., Leong, D. W., Senderek, J., Salman, M. S., Chitayat, D., Seeman, P., von Moers, A., and 14 others. <strong>Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.</strong> Nature Genet. 44: 704-708, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22544365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22544365</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22544365[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22544365">Wan et al. (2012)</a> stated that the EXOSC3 gene contains 4 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22544365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#3" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 6/25/2014."None>Gross (2014)</a> mapped the EXOSC3 gene to chromosome 9p13.2 based on an alignment of the EXOSC3 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AF281132" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AF281132</a>) with the genomic sequence (GRCh37).</p>
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<p>Using a cell-free RNA decay system, <a href="#2" class="mim-tip-reference" title="Chen, C.-Y., Gherzi, R., Ong, S.-E., Chan, E. L., Raijmakers, R., Pruijn, G. J. M., Stoecklin, G., Moroni, C., Mann, M., Karin, M. <strong>AU binding proteins recruit the exosome to degrade ARE-containing mRNAs.</strong> Cell 107: 451-464, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11719186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11719186</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00578-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11719186">Chen et al. (2001)</a> demonstrated that the mammalian exosome is required for rapid degradation of ARE-containing RNAs but not for poly(A) shortening. They found that the mammalian exosome does not recognize ARE-containing RNAs on its own. ARE recognition required certain ARE-binding proteins that could interact with the exosome and recruit it to unstable RNAs, thereby promoting their rapid degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11719186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Functional analysis by <a href="#1" class="mim-tip-reference" title="Brouwer, R., Allmang, C., Raijmakers, R., van Aarssen, Y., Egberts, W. V., Petfalski, E., van Venrooij, W. J., Tollervey, D., Pruijn, G. J. M. <strong>Three novel components of the human exosome.</strong> J. Biol. Chem. 276: 6177-6184, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11110791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11110791</a>] [<a href="https://doi.org/10.1074/jbc.M007603200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11110791">Brouwer et al. (2001)</a> supported the conclusion that RRP40 is present in human exosomes in a complex displaying 3-prime-to-5-prime exonuclease activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11110791" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 9 families with autosomal recessive pontocerebellar hypoplasia type 1B (PCH1B; <a href="/entry/614678">614678</a>), <a href="#7" class="mim-tip-reference" title="Wan, J., Yourshaw, M., Mamsa, H., Rudnik-Schoneborn, S., Menezes, M. P., Hong, J. E., Leong, D. W., Senderek, J., Salman, M. S., Chitayat, D., Seeman, P., von Moers, A., and 14 others. <strong>Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.</strong> Nature Genet. 44: 704-708, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22544365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22544365</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22544365[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22544365">Wan et al. (2012)</a> identified homozygous or compound heterozygous mutations in the EXOSC3 gene (see, e.g., <a href="#0001">606489.0001</a>-<a href="#0005">606489.0005</a>). The first mutation was identified by genomewide scan and exome sequencing of a family with 4 affected brothers. The phenotype was severe and characterized by a combination of cerebellar and spinal motor neuron degeneration beginning at birth. There was diffuse muscle weakness, progressive microcephaly, global and developmental delay, and brainstem involvement. The findings indicated that proper RNA processing is important for the development and survival of cerebellar and spinal motor neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22544365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#7" class="mim-tip-reference" title="Wan, J., Yourshaw, M., Mamsa, H., Rudnik-Schoneborn, S., Menezes, M. P., Hong, J. E., Leong, D. W., Senderek, J., Salman, M. S., Chitayat, D., Seeman, P., von Moers, A., and 14 others. <strong>Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.</strong> Nature Genet. 44: 704-708, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22544365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22544365</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22544365[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22544365">Wan et al. (2012)</a> found that morpholino knockdown of Exosc3 in zebrafish embryos caused embryonic maldevelopment, with small brain size, particularly in the hindbrain, a short and curved spine, and poor motility. There was diminished expression of dorsal hindbrain progenitor-specific markers and cerebellar-specific markers compared to controls. The defects were largely rescued by coinjection with wildtype zebrafish Exosc3 mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22544365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Pefanis, E., Wang, J., Rothschild, G., Lim, J., Chao, J., Rabadan, R., Economides, A. N., Basu, U. <strong>Noncoding RNA transcription targets AID to divergently transcribed loci in B cells.</strong> Nature 514: 389-393, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25119026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25119026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25119026[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/nature13580" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25119026">Pefanis et al. (2014)</a> generated a mouse model in which the essential subunit Exosc3 was conditionally deleted in B cells. These Exosc3-deficient B cells lacked the ability to undergo normal levels of class switch recombination and somatic hypermutation, 2 mutagenic DNA processes used to generate antibody diversity via the B-cell mutator protein AID (<a href="/entry/605257">605257</a>). The transcriptome of Exosc3-deficient B cells revealed the presence of many novel RNA exosome substrate noncoding RNAs (ncRNAs). RNA exosome substrate RNAs include xTSS-RNAs, transcription start site (TSS)-associated antisense transcripts that can exceed 500 basepairs in length and are transcribed divergently from cognate coding gene transcripts. xTSS-RNAs are most strongly expressed at genes that accumulate AID-mediated somatic mutations and/or are frequent translocation partners of DNA double-strand breaks generated at the IgG heavy chain locus (Igh; <a href="/entry/147100">147100</a>) in B cells. Strikingly, translocations near TSSs or within gene bodies occur over regions of RNA exosome substrate ncRNA expression. These RNA exosome-regulated, antisense-transcribed regions of the B-cell genome recruit AID and accumulate single-strand DNA structures containing RNA-DNA hybrids. <a href="#5" class="mim-tip-reference" title="Pefanis, E., Wang, J., Rothschild, G., Lim, J., Chao, J., Rabadan, R., Economides, A. N., Basu, U. <strong>Noncoding RNA transcription targets AID to divergently transcribed loci in B cells.</strong> Nature 514: 389-393, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25119026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25119026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25119026[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/nature13580" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25119026">Pefanis et al. (2014)</a> proposed that RNA exosome regulation of ncRNA recruits AID to single-strand DNA-forming sites of antisense and divergent transcription in the B-cell genome, thereby creating a link between ncRNA transcription and overall maintenance of B-cell genomic integrity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25119026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>7 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=606489[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs141138948 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs141138948;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs141138948?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs141138948" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs141138948" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000024366 OR RCV000190687 OR RCV000224817 OR RCV000761614 OR RCV001836713 OR RCV003156064 OR RCV004757111" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024366, RCV000190687, RCV000224817, RCV000761614, RCV001836713, RCV003156064, RCV004757111" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024366...</a>
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<p>In 4 brothers from a family of American and European ancestry with pontocerebellar hypoplasia type 1B (PCH1B; <a href="/entry/614678">614678</a>), <a href="#7" class="mim-tip-reference" title="Wan, J., Yourshaw, M., Mamsa, H., Rudnik-Schoneborn, S., Menezes, M. P., Hong, J. E., Leong, D. W., Senderek, J., Salman, M. S., Chitayat, D., Seeman, P., von Moers, A., and 14 others. <strong>Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.</strong> Nature Genet. 44: 704-708, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22544365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22544365</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22544365[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22544365">Wan et al. (2012)</a> identified a homozygous 395A-C transversion in exon 2 of the EXOSC3 gene, resulting in an asp132-to-ala (D132A) substitution in a highly conserved residue in the putative RNA-binding S1 domain, which may be important for intersubunit interaction within the exosome complex. The mutation was identified by genomewide scan and exome sequencing, and confirmed by Sanger sequencing. Sequencing of this gene identified the same homozygous mutation in affected individuals from 3 additional families with the disorder; 2 of these families were consanguineous. Haplotype analysis of 3 of the families with a homozygous D132A mutation was consistent with a remote common ancestor. Affected individuals in 3 additional families carried the D132A mutation in compound heterozygosity with another pathogenic mutation in the EXOSC3 gene (see, e.g., <a href="#0002">606489.0002</a> and <a href="#0003">606489.0003</a>). All available parents were unaffected and heterozygous for 1 of the mutations, which were not found in 379 control individuals. The phenotype consisted of neonatal onset of severe hypotonia, often with respiratory insufficiency, and global developmental delay, without achieving any motor milestones or speech, and progressive microcephaly. Other features included oculomotor apraxia, progressive muscle wasting, and distal contractures. Brain MRI showed marked cerebellar and pontine atrophy. Postmortem examination showed severe loss of cerebellar and spinal motor neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22544365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 teenaged sibs of Bangladeshi descent with PCH1B, <a href="#8" class="mim-tip-reference" title="Zanni, G., Scotton, C., Passarelli, C., Fang, M., Barresi, S., Dallapiccola, B., Wu, B., Gualandi, F., Ferlini, A., Bertini, E., Wei, W. <strong>Exome sequencing in a family with intellectual disability, early onset spasticity, and cerebellar atrophy detects a novel mutation in EXOSC3.</strong> Neurogenetics 14: 247-250, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23975261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23975261</a>] [<a href="https://doi.org/10.1007/s10048-013-0371-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23975261">Zanni et al. (2013)</a> identified compound heterozygous mutations in the EXOSC3 gene: D132A, and a c.238G-T transversion, resulting in a val80-to-phe (V80F; <a href="#0006">606489.0006</a>) substitution at a conserved residue in the N-terminal domain. The mutations were found by exome sequencing and filtered against the dbSNP (build 135) and 1000 Genomes Project databases; D132A was observed in 6 of 4,870 control exomes (allele frequency of 0.0012). The unaffected parents and 2 unaffected sibs were heterozygous for 1 of the mutations. Functional studies of the variants were not performed. The patients had a relatively mild form of the disorder, with delayed motor development, onset of spasticity in childhood, and mild to moderate intellectual disability, but without hypotonia or microcephaly. The report expanded the phenotypic spectrum associated with EXOSC3 mutations to include hereditary spastic paraplegia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23975261" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0002 PONTOCEREBELLAR HYPOPLASIA, TYPE 1B</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387907195 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907195;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387907195?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387907195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387907195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000024367 OR RCV003234918" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024367, RCV003234918" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024367...</a>
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<p>In an 11-month-old Australian boy with pontocerebellar hypoplasia type 1B (PCH1B; <a href="/entry/614678">614678</a>), <a href="#7" class="mim-tip-reference" title="Wan, J., Yourshaw, M., Mamsa, H., Rudnik-Schoneborn, S., Menezes, M. P., Hong, J. E., Leong, D. W., Senderek, J., Salman, M. S., Chitayat, D., Seeman, P., von Moers, A., and 14 others. <strong>Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.</strong> Nature Genet. 44: 704-708, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22544365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22544365</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22544365[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22544365">Wan et al. (2012)</a> identified compound heterozygosity for 2 mutations in the EXOSC3 gene: a 415G-C transversion in exon 2 resulting in an ala139-to-pro (A139P) substitution at a highly conserved residue in the RNA-binding S1 domain, and D132A (<a href="#0001">606489.0001</a>). Neither mutation was found in 379 control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22544365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 PONTOCEREBELLAR HYPOPLASIA, TYPE 1B</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs672601331 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs672601331;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs672601331" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs672601331" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a boy from New Caledonia with pontocerebellar hypoplasia type 1B (PCH1B; <a href="/entry/614678">614678</a>), <a href="#7" class="mim-tip-reference" title="Wan, J., Yourshaw, M., Mamsa, H., Rudnik-Schoneborn, S., Menezes, M. P., Hong, J. E., Leong, D. W., Senderek, J., Salman, M. S., Chitayat, D., Seeman, P., von Moers, A., and 14 others. <strong>Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.</strong> Nature Genet. 44: 704-708, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22544365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22544365</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22544365[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22544365">Wan et al. (2012)</a> identified compound heterozygosity for 2 mutations in the EXOSC3 gene: a 10-bp deletion (294_303del) in exon 1, predicted to result in premature termination (99fsTer11) or nonsense-mediated mRNA decay, and D132A (<a href="#0001">606489.0001</a>). Neither mutation was found in 379 control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22544365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 PONTOCEREBELLAR HYPOPLASIA, TYPE 1B</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387907196 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907196;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387907196?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387907196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387907196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000024369 OR RCV000853550 OR RCV001092265 OR RCV004586024" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024369, RCV000853550, RCV001092265, RCV004586024" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024369...</a>
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<p>In 2 Czech sibs with pontocerebellar hypoplasia type 1B (PCH1B; <a href="/entry/614678">614678</a>), <a href="#7" class="mim-tip-reference" title="Wan, J., Yourshaw, M., Mamsa, H., Rudnik-Schoneborn, S., Menezes, M. P., Hong, J. E., Leong, D. W., Senderek, J., Salman, M. S., Chitayat, D., Seeman, P., von Moers, A., and 14 others. <strong>Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.</strong> Nature Genet. 44: 704-708, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22544365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22544365</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22544365[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22544365">Wan et al. (2012)</a> identified compound heterozygosity for 2 mutations in the EXOSC3 gene: a 92G-C transversion in exon 1, resulting in a gly31-to-ala (G31A) substitution at a highly conserved residue in the N-terminal domain, and a 712T-C transition in exon 4, resulting in a trp238-to-arg (W238R; <a href="#0005">606489.0005</a>) substitution at a highly conserved residue in the putative RNA-binding KH domain. Another unrelated Czech boy with the disorder was homozygous for the G31A mutation. Neither mutation was found in 379 control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22544365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Schwabova, J., Brozkova, D. S., Petrak, B., Mojzisova, M., Pavlickova, K., Haberlova, J., Mrazkova, L., Hedvicakova, P., Hornofova, L., Kaluzova, M., Fencl, F., Krutova, M., Zamecnik, J., Seeman, P. <strong>Homozygous EXOSC3 mutation c.92G-C, p.G31A is a founder mutation causing severe pontocerebellar hypoplasia type 1 among the Czech Roma.</strong> J. Neurogenet. 27: 163-169, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23883322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23883322</a>] [<a href="https://doi.org/10.3109/01677063.2013.814651" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23883322">Schwabova et al. (2013)</a> identified a homozygous G31A mutation in 2 unrelated Czech children of Roma descent with PCH1B. The heterozygous mutation was found in 4 (4.4%) of 90 unrelated Roma control individuals, and haplotype analysis suggested a founder effect. The patients had a severe form of the disorder, with death in the first year of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23883322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 PONTOCEREBELLAR HYPOPLASIA, TYPE 1B</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs672601332 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs672601332;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs672601332" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs672601332" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the trp238-to-arg (W238R) mutation in the EXOSC3 gene that was found in compound heterozygous state in 2 patients with pontocerebellar hypoplasia type 1B (PCH1B; <a href="/entry/614678">614678</a>) by <a href="#7" class="mim-tip-reference" title="Wan, J., Yourshaw, M., Mamsa, H., Rudnik-Schoneborn, S., Menezes, M. P., Hong, J. E., Leong, D. W., Senderek, J., Salman, M. S., Chitayat, D., Seeman, P., von Moers, A., and 14 others. <strong>Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.</strong> Nature Genet. 44: 704-708, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22544365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22544365</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22544365[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22544365">Wan et al. (2012)</a>, see <a href="#0004">606489.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22544365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 PONTOCEREBELLAR HYPOPLASIA, TYPE 1B</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs374550999 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs374550999;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs374550999?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs374550999" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs374550999" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000117005 OR RCV000825519 OR RCV001200535" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000117005, RCV000825519, RCV001200535" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000117005...</a>
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<p>For discussion of the val80-to-phe (V80F) mutation in the EXOSC3 gene that was found in compound heterozygous state in 2 patients with pontocerebellar hypoplasia type 1B (PCH1B; <a href="/entry/614678">614678</a>) by <a href="#8" class="mim-tip-reference" title="Zanni, G., Scotton, C., Passarelli, C., Fang, M., Barresi, S., Dallapiccola, B., Wu, B., Gualandi, F., Ferlini, A., Bertini, E., Wei, W. <strong>Exome sequencing in a family with intellectual disability, early onset spasticity, and cerebellar atrophy detects a novel mutation in EXOSC3.</strong> Neurogenetics 14: 247-250, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23975261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23975261</a>] [<a href="https://doi.org/10.1007/s10048-013-0371-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23975261">Zanni et al. (2013)</a>, see <a href="#0001">606489.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23975261" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs730882145 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs730882145;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs730882145?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs730882145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs730882145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000161917" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000161917" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000161917</a>
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<p>In 2 pairs of sibs from a large consanguineous family of Arab origin with a mild form of pontocerebellar hypoplasia type 1B (PCH1B; <a href="/entry/614678">614678</a>) presenting as complicated hereditary spastic paraplegia with variable cognitive impairment, <a href="#4" class="mim-tip-reference" title="Halevy, A., Lerer, I., Cohen, R., Kornreich, L., Shuper, A., Gamliel, M., Zimerman, B.-E., Korabi, I., Meiner, V., Straussberg, R., Lossos, A. <strong>Novel EXOSC3 mutation causes complicated hereditary spastic paraplegia.</strong> J. Neurol. 261: 2165-2169, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25149867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25149867</a>] [<a href="https://doi.org/10.1007/s00415-014-7457-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25149867">Halevy et al. (2014)</a> identified a homozygous c.571G-T transversion in the EXOSC3 gene, resulting in a gly191-to-cys (G191C) substitution at a conserved residue in the S1-like domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder in both families. It was not present in the dbSNP (build 129) or 1000 Genomes Project databases. Functional studies of the variant were not performed. The patients were 12 to 21 years of age at the time of the report. All patients had mild cerebellar signs, including nystagmus with or without intention tremor and dysmetria, and brain imaging of all patients showed mild hypoplasia and atrophy of the lower part of the vermis with a normal pons. None had microcephaly or lower motor neuron signs, and spinal imaging was normal. <a href="#4" class="mim-tip-reference" title="Halevy, A., Lerer, I., Cohen, R., Kornreich, L., Shuper, A., Gamliel, M., Zimerman, B.-E., Korabi, I., Meiner, V., Straussberg, R., Lossos, A. <strong>Novel EXOSC3 mutation causes complicated hereditary spastic paraplegia.</strong> J. Neurol. 261: 2165-2169, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25149867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25149867</a>] [<a href="https://doi.org/10.1007/s00415-014-7457-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25149867">Halevy et al. (2014)</a> emphasized the mild phenotype in these patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25149867" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Three novel components of the human exosome.</strong>
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J. Biol. Chem. 276: 6177-6184, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11110791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11110791</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11110791" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Chen, C.-Y., Gherzi, R., Ong, S.-E., Chan, E. L., Raijmakers, R., Pruijn, G. J. M., Stoecklin, G., Moroni, C., Mann, M., Karin, M.
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<strong>AU binding proteins recruit the exosome to degrade ARE-containing mRNAs.</strong>
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Cell 107: 451-464, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11719186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11719186</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11719186" 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/s0092-8674(01)00578-5" target="_blank">Full Text</a>]
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<a id="Halevy2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Halevy, A., Lerer, I., Cohen, R., Kornreich, L., Shuper, A., Gamliel, M., Zimerman, B.-E., Korabi, I., Meiner, V., Straussberg, R., Lossos, A.
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<strong>Novel EXOSC3 mutation causes complicated hereditary spastic paraplegia.</strong>
|
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J. Neurol. 261: 2165-2169, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25149867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25149867</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25149867" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00415-014-7457-x" 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="5" class="mim-anchor"></a>
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<a id="Pefanis2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pefanis, E., Wang, J., Rothschild, G., Lim, J., Chao, J., Rabadan, R., Economides, A. N., Basu, U.
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<strong>Noncoding RNA transcription targets AID to divergently transcribed loci in B cells.</strong>
|
|
Nature 514: 389-393, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25119026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25119026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25119026[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=25119026" 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/nature13580" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="Schwabova2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Schwabova, J., Brozkova, D. S., Petrak, B., Mojzisova, M., Pavlickova, K., Haberlova, J., Mrazkova, L., Hedvicakova, P., Hornofova, L., Kaluzova, M., Fencl, F., Krutova, M., Zamecnik, J., Seeman, P.
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|
<strong>Homozygous EXOSC3 mutation c.92G-C, p.G31A is a founder mutation causing severe pontocerebellar hypoplasia type 1 among the Czech Roma.</strong>
|
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J. Neurogenet. 27: 163-169, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23883322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23883322</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23883322" 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/10.3109/01677063.2013.814651" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="Wan2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wan, J., Yourshaw, M., Mamsa, H., Rudnik-Schoneborn, S., Menezes, M. P., Hong, J. E., Leong, D. W., Senderek, J., Salman, M. S., Chitayat, D., Seeman, P., von Moers, A., and 14 others.
|
|
<strong>Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.</strong>
|
|
Nature Genet. 44: 704-708, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22544365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22544365</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22544365[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=22544365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.2254" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Zanni2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zanni, G., Scotton, C., Passarelli, C., Fang, M., Barresi, S., Dallapiccola, B., Wu, B., Gualandi, F., Ferlini, A., Bertini, E., Wei, W.
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<strong>Exome sequencing in a family with intellectual disability, early onset spasticity, and cerebellar atrophy detects a novel mutation in EXOSC3.</strong>
|
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Neurogenetics 14: 247-250, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23975261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23975261</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23975261" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10048-013-0371-z" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 2/18/2015
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/8/2014<br>Ada Hamosh - updated : 11/5/2014<br>Matthew B. Gross - updated : 6/25/2014<br>Cassandra L. Kniffin - updated : 6/7/2012<br>Paul J. Converse - updated : 10/23/2002
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Stylianos E. Antonarakis : 11/26/2001
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</span>
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</div>
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</div>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 04/06/2015
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 2/24/2015<br>mcolton : 2/18/2015<br>ckniffin : 2/18/2015<br>mcolton : 2/4/2015<br>carol : 12/15/2014<br>mcolton : 12/10/2014<br>ckniffin : 12/8/2014<br>alopez : 11/5/2014<br>mgross : 6/25/2014<br>carol : 6/8/2012<br>ckniffin : 6/7/2012<br>carol : 5/10/2005<br>mgross : 10/23/2002<br>mgross : 10/23/2002<br>mgross : 11/26/2001
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</span>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 606489
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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EXOSOME COMPONENT 3; EXOSC3
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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RIBOSOMAL RNA-PROCESSING PROTEIN 40, S. CEREVISIAE, HOMOLOG OF; RRP40
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: EXOSC3</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 9p13.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 9:37,779,714-37,785,092 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed 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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9p13.2
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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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Pontocerebellar hypoplasia, type 1B
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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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614678
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
|
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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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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The EXOSC3 gene encodes a core component of the human RNA exosome complex that is present in the cytoplasm and the nucleus and especially enriched in the nucleolus (Brouwer et al., 2001). </p>
|
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Cloning and Expression</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Inherently unstable mammalian mRNAs contain AU-rich elements (AREs) within their 3-prime untranslated regions. In yeast, 3-prime-to-5-prime mRNA degradation is mediated by the exosome, a multisubunit particle. Chen et al. (2001) purified and characterized the human exosome by mass spectrometry and found its composition to be similar to its yeast counterpart. They identified the following protein subunits within the human exosome: p7, which is homologous to the yeast Rrp4 protein (602238); p8, which is homologous to the yeast Rrp42 protein (606488); p9, which is homologous to the yeast Rrp43 protein (OIP2; 606019); p10, which is homologous to the yeast Rrp40 protein; p11, which is homologous to the yeast Mtr3 protein (606490); p12A, which is homologous to the yeast Rrp41 protein (606491); p12B, which is homologous to the yeast Rrp46 protein (606492); and p13, which is homologous to the yeast Csl4 protein (606493). They also identified 2 exosome-associated factors, p1 (600478) and p14 (MPP6; 605500), that were not homologous to any yeast exosome components. </p><p>By searching an EST database for homologs of yeast exosome components, followed by PCR on a teratocarcinoma cell line and 5-prime RACE using placenta RNA, Brouwer et al. (2001) isolated cDNAs encoding RRP40, RRP41, and RRP46. The deduced 275-amino acid RRP40 protein is 88% and 30% identical to the mouse and yeast sequences, respectively. Western blot analysis and immunofluorescence microscopy showed expression of a 31-kD protein in the nucleus, with additional forms expressed in the cytoplasm and the highest concentration in nucleolus. </p><p>There are multiple alternatively spliced forms of EXOSC3, with the longest reading frame encoding a 275-residue protein (summary by Wan et al., 2012). </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">
|
|
<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>Wan et al. (2012) stated that the EXOSC3 gene contains 4 exons. </p>
|
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</span>
|
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<div>
|
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<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">
|
|
<p>Gross (2014) mapped the EXOSC3 gene to chromosome 9p13.2 based on an alignment of the EXOSC3 sequence (GenBank AF281132) with the genomic sequence (GRCh37).</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Using a cell-free RNA decay system, Chen et al. (2001) demonstrated that the mammalian exosome is required for rapid degradation of ARE-containing RNAs but not for poly(A) shortening. They found that the mammalian exosome does not recognize ARE-containing RNAs on its own. ARE recognition required certain ARE-binding proteins that could interact with the exosome and recruit it to unstable RNAs, thereby promoting their rapid degradation. </p><p>Functional analysis by Brouwer et al. (2001) supported the conclusion that RRP40 is present in human exosomes in a complex displaying 3-prime-to-5-prime exonuclease activity. </p>
|
|
</span>
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<div>
|
|
<br />
|
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</div>
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<div>
|
|
<h4>
|
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<span class="mim-font">
|
|
<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 9 families with autosomal recessive pontocerebellar hypoplasia type 1B (PCH1B; 614678), Wan et al. (2012) identified homozygous or compound heterozygous mutations in the EXOSC3 gene (see, e.g., 606489.0001-606489.0005). The first mutation was identified by genomewide scan and exome sequencing of a family with 4 affected brothers. The phenotype was severe and characterized by a combination of cerebellar and spinal motor neuron degeneration beginning at birth. There was diffuse muscle weakness, progressive microcephaly, global and developmental delay, and brainstem involvement. The findings indicated that proper RNA processing is important for the development and survival of cerebellar and spinal motor neurons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Wan et al. (2012) found that morpholino knockdown of Exosc3 in zebrafish embryos caused embryonic maldevelopment, with small brain size, particularly in the hindbrain, a short and curved spine, and poor motility. There was diminished expression of dorsal hindbrain progenitor-specific markers and cerebellar-specific markers compared to controls. The defects were largely rescued by coinjection with wildtype zebrafish Exosc3 mRNA. </p><p>Pefanis et al. (2014) generated a mouse model in which the essential subunit Exosc3 was conditionally deleted in B cells. These Exosc3-deficient B cells lacked the ability to undergo normal levels of class switch recombination and somatic hypermutation, 2 mutagenic DNA processes used to generate antibody diversity via the B-cell mutator protein AID (605257). The transcriptome of Exosc3-deficient B cells revealed the presence of many novel RNA exosome substrate noncoding RNAs (ncRNAs). RNA exosome substrate RNAs include xTSS-RNAs, transcription start site (TSS)-associated antisense transcripts that can exceed 500 basepairs in length and are transcribed divergently from cognate coding gene transcripts. xTSS-RNAs are most strongly expressed at genes that accumulate AID-mediated somatic mutations and/or are frequent translocation partners of DNA double-strand breaks generated at the IgG heavy chain locus (Igh; 147100) in B cells. Strikingly, translocations near TSSs or within gene bodies occur over regions of RNA exosome substrate ncRNA expression. These RNA exosome-regulated, antisense-transcribed regions of the B-cell genome recruit AID and accumulate single-strand DNA structures containing RNA-DNA hybrids. Pefanis et al. (2014) proposed that RNA exosome regulation of ncRNA recruits AID to single-strand DNA-forming sites of antisense and divergent transcription in the B-cell genome, thereby creating a link between ncRNA transcription and overall maintenance of B-cell genomic integrity. </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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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>7 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 PONTOCEREBELLAR HYPOPLASIA, TYPE 1B</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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EXOSC3, ASP132ALA
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<br />
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SNP: rs141138948,
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gnomAD: rs141138948,
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ClinVar: RCV000024366, RCV000190687, RCV000224817, RCV000761614, RCV001836713, RCV003156064, RCV004757111
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 4 brothers from a family of American and European ancestry with pontocerebellar hypoplasia type 1B (PCH1B; 614678), Wan et al. (2012) identified a homozygous 395A-C transversion in exon 2 of the EXOSC3 gene, resulting in an asp132-to-ala (D132A) substitution in a highly conserved residue in the putative RNA-binding S1 domain, which may be important for intersubunit interaction within the exosome complex. The mutation was identified by genomewide scan and exome sequencing, and confirmed by Sanger sequencing. Sequencing of this gene identified the same homozygous mutation in affected individuals from 3 additional families with the disorder; 2 of these families were consanguineous. Haplotype analysis of 3 of the families with a homozygous D132A mutation was consistent with a remote common ancestor. Affected individuals in 3 additional families carried the D132A mutation in compound heterozygosity with another pathogenic mutation in the EXOSC3 gene (see, e.g., 606489.0002 and 606489.0003). All available parents were unaffected and heterozygous for 1 of the mutations, which were not found in 379 control individuals. The phenotype consisted of neonatal onset of severe hypotonia, often with respiratory insufficiency, and global developmental delay, without achieving any motor milestones or speech, and progressive microcephaly. Other features included oculomotor apraxia, progressive muscle wasting, and distal contractures. Brain MRI showed marked cerebellar and pontine atrophy. Postmortem examination showed severe loss of cerebellar and spinal motor neurons. </p><p>In 2 teenaged sibs of Bangladeshi descent with PCH1B, Zanni et al. (2013) identified compound heterozygous mutations in the EXOSC3 gene: D132A, and a c.238G-T transversion, resulting in a val80-to-phe (V80F; 606489.0006) substitution at a conserved residue in the N-terminal domain. The mutations were found by exome sequencing and filtered against the dbSNP (build 135) and 1000 Genomes Project databases; D132A was observed in 6 of 4,870 control exomes (allele frequency of 0.0012). The unaffected parents and 2 unaffected sibs were heterozygous for 1 of the mutations. Functional studies of the variants were not performed. The patients had a relatively mild form of the disorder, with delayed motor development, onset of spasticity in childhood, and mild to moderate intellectual disability, but without hypotonia or microcephaly. The report expanded the phenotypic spectrum associated with EXOSC3 mutations to include hereditary spastic paraplegia. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 PONTOCEREBELLAR HYPOPLASIA, TYPE 1B</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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EXOSC3, ALA139PRO
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<br />
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SNP: rs387907195,
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gnomAD: rs387907195,
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ClinVar: RCV000024367, RCV003234918
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In an 11-month-old Australian boy with pontocerebellar hypoplasia type 1B (PCH1B; 614678), Wan et al. (2012) identified compound heterozygosity for 2 mutations in the EXOSC3 gene: a 415G-C transversion in exon 2 resulting in an ala139-to-pro (A139P) substitution at a highly conserved residue in the RNA-binding S1 domain, and D132A (606489.0001). Neither mutation was found in 379 control individuals. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0003 PONTOCEREBELLAR HYPOPLASIA, TYPE 1B</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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EXOSC3, 10-BP DEL, NT294
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<br />
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SNP: rs672601331,
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ClinVar: RCV000024368
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a boy from New Caledonia with pontocerebellar hypoplasia type 1B (PCH1B; 614678), Wan et al. (2012) identified compound heterozygosity for 2 mutations in the EXOSC3 gene: a 10-bp deletion (294_303del) in exon 1, predicted to result in premature termination (99fsTer11) or nonsense-mediated mRNA decay, and D132A (606489.0001). Neither mutation was found in 379 control individuals. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 PONTOCEREBELLAR HYPOPLASIA, TYPE 1B</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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EXOSC3, GLY31ALA
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<br />
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SNP: rs387907196,
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gnomAD: rs387907196,
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|
|
ClinVar: RCV000024369, RCV000853550, RCV001092265, RCV004586024
|
|
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|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Czech sibs with pontocerebellar hypoplasia type 1B (PCH1B; 614678), Wan et al. (2012) identified compound heterozygosity for 2 mutations in the EXOSC3 gene: a 92G-C transversion in exon 1, resulting in a gly31-to-ala (G31A) substitution at a highly conserved residue in the N-terminal domain, and a 712T-C transition in exon 4, resulting in a trp238-to-arg (W238R; 606489.0005) substitution at a highly conserved residue in the putative RNA-binding KH domain. Another unrelated Czech boy with the disorder was homozygous for the G31A mutation. Neither mutation was found in 379 control individuals. </p><p>Schwabova et al. (2013) identified a homozygous G31A mutation in 2 unrelated Czech children of Roma descent with PCH1B. The heterozygous mutation was found in 4 (4.4%) of 90 unrelated Roma control individuals, and haplotype analysis suggested a founder effect. The patients had a severe form of the disorder, with death in the first year of life. </p>
|
|
</span>
|
|
</div>
|
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|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 PONTOCEREBELLAR HYPOPLASIA, TYPE 1B</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
EXOSC3, TRP238ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs672601332,
|
|
|
|
|
|
|
|
ClinVar: RCV000024370
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the trp238-to-arg (W238R) mutation in the EXOSC3 gene that was found in compound heterozygous state in 2 patients with pontocerebellar hypoplasia type 1B (PCH1B; 614678) by Wan et al. (2012), see 606489.0004. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 PONTOCEREBELLAR HYPOPLASIA, TYPE 1B</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
EXOSC3, VAL80PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs374550999,
|
|
|
|
|
|
gnomAD: rs374550999,
|
|
|
|
|
|
ClinVar: RCV000117005, RCV000825519, RCV001200535
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the val80-to-phe (V80F) mutation in the EXOSC3 gene that was found in compound heterozygous state in 2 patients with pontocerebellar hypoplasia type 1B (PCH1B; 614678) by Zanni et al. (2013), see 606489.0001. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 PONTOCEREBELLAR HYPOPLASIA, TYPE 1B</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
EXOSC3, GLY191CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs730882145,
|
|
|
|
|
|
gnomAD: rs730882145,
|
|
|
|
|
|
ClinVar: RCV000161917
|
|
|
|
|
|
</span>
|
|
</div>
|
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|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 pairs of sibs from a large consanguineous family of Arab origin with a mild form of pontocerebellar hypoplasia type 1B (PCH1B; 614678) presenting as complicated hereditary spastic paraplegia with variable cognitive impairment, Halevy et al. (2014) identified a homozygous c.571G-T transversion in the EXOSC3 gene, resulting in a gly191-to-cys (G191C) substitution at a conserved residue in the S1-like domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder in both families. It was not present in the dbSNP (build 129) or 1000 Genomes Project databases. Functional studies of the variant were not performed. The patients were 12 to 21 years of age at the time of the report. All patients had mild cerebellar signs, including nystagmus with or without intention tremor and dysmetria, and brain imaging of all patients showed mild hypoplasia and atrophy of the lower part of the vermis with a normal pons. None had microcephaly or lower motor neuron signs, and spinal imaging was normal. Halevy et al. (2014) emphasized the mild phenotype in these patients. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
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</h4>
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<div>
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
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Brouwer, R., Allmang, C., Raijmakers, R., van Aarssen, Y., Egberts, W. V., Petfalski, E., van Venrooij, W. J., Tollervey, D., Pruijn, G. J. M.
|
|
<strong>Three novel components of the human exosome.</strong>
|
|
J. Biol. Chem. 276: 6177-6184, 2001.
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[PubMed: 11110791]
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[Full Text: https://doi.org/10.1074/jbc.M007603200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Chen, C.-Y., Gherzi, R., Ong, S.-E., Chan, E. L., Raijmakers, R., Pruijn, G. J. M., Stoecklin, G., Moroni, C., Mann, M., Karin, M.
|
|
<strong>AU binding proteins recruit the exosome to degrade ARE-containing mRNAs.</strong>
|
|
Cell 107: 451-464, 2001.
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[PubMed: 11719186]
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[Full Text: https://doi.org/10.1016/s0092-8674(01)00578-5]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Gross, M. B.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 6/25/2014.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Halevy, A., Lerer, I., Cohen, R., Kornreich, L., Shuper, A., Gamliel, M., Zimerman, B.-E., Korabi, I., Meiner, V., Straussberg, R., Lossos, A.
|
|
<strong>Novel EXOSC3 mutation causes complicated hereditary spastic paraplegia.</strong>
|
|
J. Neurol. 261: 2165-2169, 2014.
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[PubMed: 25149867]
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[Full Text: https://doi.org/10.1007/s00415-014-7457-x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Pefanis, E., Wang, J., Rothschild, G., Lim, J., Chao, J., Rabadan, R., Economides, A. N., Basu, U.
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|
<strong>Noncoding RNA transcription targets AID to divergently transcribed loci in B cells.</strong>
|
|
Nature 514: 389-393, 2014.
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|
[PubMed: 25119026]
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[Full Text: https://doi.org/10.1038/nature13580]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Schwabova, J., Brozkova, D. S., Petrak, B., Mojzisova, M., Pavlickova, K., Haberlova, J., Mrazkova, L., Hedvicakova, P., Hornofova, L., Kaluzova, M., Fencl, F., Krutova, M., Zamecnik, J., Seeman, P.
|
|
<strong>Homozygous EXOSC3 mutation c.92G-C, p.G31A is a founder mutation causing severe pontocerebellar hypoplasia type 1 among the Czech Roma.</strong>
|
|
J. Neurogenet. 27: 163-169, 2013.
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[PubMed: 23883322]
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[Full Text: https://doi.org/10.3109/01677063.2013.814651]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Wan, J., Yourshaw, M., Mamsa, H., Rudnik-Schoneborn, S., Menezes, M. P., Hong, J. E., Leong, D. W., Senderek, J., Salman, M. S., Chitayat, D., Seeman, P., von Moers, A., and 14 others.
|
|
<strong>Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.</strong>
|
|
Nature Genet. 44: 704-708, 2012.
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[PubMed: 22544365]
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[Full Text: https://doi.org/10.1038/ng.2254]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Zanni, G., Scotton, C., Passarelli, C., Fang, M., Barresi, S., Dallapiccola, B., Wu, B., Gualandi, F., Ferlini, A., Bertini, E., Wei, W.
|
|
<strong>Exome sequencing in a family with intellectual disability, early onset spasticity, and cerebellar atrophy detects a novel mutation in EXOSC3.</strong>
|
|
Neurogenetics 14: 247-250, 2013.
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[PubMed: 23975261]
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[Full Text: https://doi.org/10.1007/s10048-013-0371-z]
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</p>
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</li>
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</ol>
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Cassandra L. Kniffin - updated : 2/18/2015<br>Cassandra L. Kniffin - updated : 12/8/2014<br>Ada Hamosh - updated : 11/5/2014<br>Matthew B. Gross - updated : 6/25/2014<br>Cassandra L. Kniffin - updated : 6/7/2012<br>Paul J. Converse - updated : 10/23/2002
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carol : 04/06/2015<br>carol : 2/24/2015<br>mcolton : 2/18/2015<br>ckniffin : 2/18/2015<br>mcolton : 2/4/2015<br>carol : 12/15/2014<br>mcolton : 12/10/2014<br>ckniffin : 12/8/2014<br>alopez : 11/5/2014<br>mgross : 6/25/2014<br>carol : 6/8/2012<br>ckniffin : 6/7/2012<br>carol : 5/10/2005<br>mgross : 10/23/2002<br>mgross : 10/23/2002<br>mgross : 11/26/2001
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