4740 lines
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Entry
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- *606609 - 3-PRIME REPAIR EXONUCLEASE 1; TREX1
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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">*606609</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<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/606609">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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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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<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=ENSG00000213689;t=ENST00000625293" 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=11277" 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=606609" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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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=ENSG00000213689;t=ENST00000625293" 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_007248,NM_033629" 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_033629" 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=606609" 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=09423&isoform_id=09423_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/TREX1" 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/5524927,17865433,18375535,18921087,23272145,48146355,54696966,54696968,119585287,189054807,404434375,444738949,1316032202" 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/Q9NSU2" 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=11277" 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=ENSG00000213689;t=ENST00000625293" 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=TREX1" 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=TREX1" 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+11277" 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/TREX1" 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:11277" 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/11277" 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=chr3&hgg_gene=ENST00000625293.3&hgg_start=48465830&hgg_end=48467645&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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:12269" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/trex1" 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=606609[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=606609[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/TREX1/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/ENSG00000213689" 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=TREX1" 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=TREX1" 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=TREX1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/TREX1" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=TREX1&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/PA36949" 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:12269" 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/FBgn0031484.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:1328317" 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/TREX1#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:1328317" 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/11277/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=11277" 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=WBGene00020949;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>
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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:11277" 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=TREX1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 783787000<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
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606609
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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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3-PRIME REPAIR EXONUCLEASE 1; TREX1
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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">
|
|
DNase III
|
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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">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TREX1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TREX1</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/3/281?start=-3&limit=10&highlight=281">3p21.31</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:48465830-48467645&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'})">3:48,465,830-48,467,645</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=152700,225750,610448,192315" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
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|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/3/281?start=-3&limit=10&highlight=281">
|
|
3p21.31
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Systemic lupus erythematosus, susceptibility to}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/152700"> 152700 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Aicardi-Goutieres syndrome 1, dominant and recessive
|
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|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/225750"> 225750 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
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<p>The multistep processes of DNA replication, repair, and recombination require the excision of nucleotides from DNA 3-prime termini. Enzymes containing 3-prime-to-5-prime exonuclease activity remove mismatched, modified, fragmented, and normal nucleotides to generate the appropriate 3-prime termini for subsequent steps in the DNA metabolic pathways (<a href="#16" class="mim-tip-reference" title="Mazur, D. J., Perrino, F. W. <strong>Identification and expression of the TREX1 and TREX2 cDNA sequences encoding mammalian 3-prime-to-5-prime exonucleases.</strong> J. Biol. Chem. 274: 19655-19660, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10391904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10391904</a>] [<a href="https://doi.org/10.1074/jbc.274.28.19655" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10391904">Mazur and Perrino, 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10391904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By micropeptide sequence analysis of the 30-kD bovine Trex1 protein, PCR with degenerate primers, and EST database searching, <a href="#16" class="mim-tip-reference" title="Mazur, D. J., Perrino, F. W. <strong>Identification and expression of the TREX1 and TREX2 cDNA sequences encoding mammalian 3-prime-to-5-prime exonucleases.</strong> J. Biol. Chem. 274: 19655-19660, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10391904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10391904</a>] [<a href="https://doi.org/10.1074/jbc.274.28.19655" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10391904">Mazur and Perrino (1999)</a> obtained cDNAs encoding mouse and human TREX1 and TREX2 (<a href="/entry/300370">300370</a>). Sequence analysis predicted that the 304-amino acid TREX1 protein is 44% identical to TREX2 (<a href="#17" class="mim-tip-reference" title="Mazur, D. J., Perrino, F. W. <strong>Structure and expression of the TREX1 and TREX2 3-prime-to-5-prime exonuclease genes.</strong> J. Biol. Chem. 276: 14718-14727, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11278605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11278605</a>] [<a href="https://doi.org/10.1074/jbc.M010051200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11278605">Mazur and Perrino (2001)</a> corrected the TREX1 sequence to 314 amino acids). TREX1 contains 3 conserved exonuclease motifs, with an HxAxxD sequence in the third motif. Functional analysis confirmed that the 3-prime-to-5-prime exonuclease activity of the recombinant protein is comparable to that of the native protein and prefers mismatched 3-prime termini. <a href="#16" class="mim-tip-reference" title="Mazur, D. J., Perrino, F. W. <strong>Identification and expression of the TREX1 and TREX2 cDNA sequences encoding mammalian 3-prime-to-5-prime exonucleases.</strong> J. Biol. Chem. 274: 19655-19660, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10391904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10391904</a>] [<a href="https://doi.org/10.1074/jbc.274.28.19655" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10391904">Mazur and Perrino (1999)</a> concluded that the TREX proteins are small, independent 3-prime excision enzymes, whereas the multifunctional p53 (<a href="/entry/191170">191170</a>) and WRN (RECQL2; <a href="/entry/604611">604611</a>) proteins, which also have 3-prime-to-5-prime exonuclease activity, are much larger. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10391904+11278605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using rabbit Trex1 to search an EST database, <a href="#9" class="mim-tip-reference" title="Hoss, M., Robins, P., Naven, T. J. P., Pappin, D. J. C., Sgouros, J., Lindahl, T. <strong>A human DNA editing enzyme homologous to the Escherichia coli DnaQ/MutD protein.</strong> EMBO J. 18: 3868-3875, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10393201/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10393201</a>] [<a href="https://doi.org/10.1093/emboj/18.13.3868" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10393201">Hoss et al. (1999)</a> also isolated human TREX1, which they termed DNase III. Northern blot analysis revealed expression of a 1.15-kb TREX1 transcript in all tissues tested. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10393201" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Mazur, D. J., Perrino, F. W. <strong>Structure and expression of the TREX1 and TREX2 3-prime-to-5-prime exonuclease genes.</strong> J. Biol. Chem. 276: 14718-14727, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11278605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11278605</a>] [<a href="https://doi.org/10.1074/jbc.M010051200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11278605">Mazur and Perrino (2001)</a> used 5-prime RACE to identify the flanking region of TREX1. Genomic sequence analysis suggested that TREX1 open reading frames are produced by a variety of mechanisms, including alternate promoter usage, alternative splicing, and varied sites for 3-prime cleavage. RT-PCR analysis detected ubiquitous expression of TREX1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11278605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The TREX1 gene contains a single exon (<a href="#9" class="mim-tip-reference" title="Hoss, M., Robins, P., Naven, T. J. P., Pappin, D. J. C., Sgouros, J., Lindahl, T. <strong>A human DNA editing enzyme homologous to the Escherichia coli DnaQ/MutD protein.</strong> EMBO J. 18: 3868-3875, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10393201/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10393201</a>] [<a href="https://doi.org/10.1093/emboj/18.13.3868" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10393201">Hoss et al., 1999</a>; <a href="#17" class="mim-tip-reference" title="Mazur, D. J., Perrino, F. W. <strong>Structure and expression of the TREX1 and TREX2 3-prime-to-5-prime exonuclease genes.</strong> J. Biol. Chem. 276: 14718-14727, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11278605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11278605</a>] [<a href="https://doi.org/10.1074/jbc.M010051200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11278605">Mazur and Perrino, 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10393201+11278605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Hoss, M., Robins, P., Naven, T. J. P., Pappin, D. J. C., Sgouros, J., Lindahl, T. <strong>A human DNA editing enzyme homologous to the Escherichia coli DnaQ/MutD protein.</strong> EMBO J. 18: 3868-3875, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10393201/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10393201</a>] [<a href="https://doi.org/10.1093/emboj/18.13.3868" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10393201">Hoss et al. (1999)</a> and <a href="#17" class="mim-tip-reference" title="Mazur, D. J., Perrino, F. W. <strong>Structure and expression of the TREX1 and TREX2 3-prime-to-5-prime exonuclease genes.</strong> J. Biol. Chem. 276: 14718-14727, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11278605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11278605</a>] [<a href="https://doi.org/10.1074/jbc.M010051200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11278605">Mazur and Perrino (2001)</a> identified clones containing the TREX1 gene that map to chromosome 3p21.3-p21.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10393201+11278605" 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>SET (<a href="/entry/600960">600960</a>) and NM23H1 (NME1; <a href="/entry/156490">156490</a>) reside in an endoplasmic reticulum-associated complex, the SET complex, that translocates to the nucleus in response to superoxide generation by granzyme A (GZMA; <a href="/entry/140050">140050</a>). <a href="#3" class="mim-tip-reference" title="Chowdhury, D., Beresford, P. J., Zhu, P., Zhang, D., Sung, J.-S., Demple, B., Perrino, F. W., Lieberman, J. <strong>The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death.</strong> Molec. Cell 23: 133-142, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16818237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16818237</a>] [<a href="https://doi.org/10.1016/j.molcel.2006.06.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16818237">Chowdhury et al. (2006)</a> identified TREX1 as a component of the SET complex. TREX1 bound SET and colocalized and translocated with the SET complex. On its own, TREX1 did not damage intact DNA, but it acted in concert with NM23H1 to destroy DNA during granzyme A-mediated cell death. After NM23H1 nicked 1 strand, TREX1 removed bases from the free 3-prime end to enhance the damage and prevent DNA end reannealing and repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16818237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using mass spectrometry and Western blot analysis, <a href="#24" class="mim-tip-reference" title="Stetson, D. B., Ko, J. S., Heidmann, T., Medzhitov, R. <strong>Trex1 prevents cell-intrinsic initiation of autoimmunity.</strong> Cell 134: 587-598, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18724932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18724932</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18724932[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2008.06.032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18724932">Stetson et al. (2008)</a> identified mouse Trex1 as a protein involved in recognition of interferon stimulatory DNA (ISD) BrdU-labeled intracellular oligonucleotides. Microarray analysis showed that Trex1 was upregulated in response to ISD stimulation. However, Trex1 -/- cells retained an intact ISD response, ruling out Trex1 as the ISD sensor. In contrast with Trex1 -/- mice, which succumb to lethal autoimmunity (see ANIMAL MODEL), Trex1 -/- mice lacking Irf3 (<a href="/entry/603734">603734</a>), Ifnar1 (<a href="/entry/107450">107450</a>), or Rag2 (<a href="/entry/179616">179616</a>) survived and regained normal body weight through amelioration of disease at discrete phases, indicating that TREX1 substrates are ligands of the ISD pathway. Single-stranded DNA derived from endogenous retroelements accumulated in Trex1 -/- cells, and Trex1 metabolized reverse-transcribed DNA. <a href="#24" class="mim-tip-reference" title="Stetson, D. B., Ko, J. S., Heidmann, T., Medzhitov, R. <strong>Trex1 prevents cell-intrinsic initiation of autoimmunity.</strong> Cell 134: 587-598, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18724932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18724932</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18724932[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2008.06.032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18724932">Stetson et al. (2008)</a> concluded that TREX1 is an essential negative regulator of the ISD response and represents a mechanism to prevent autoimmunity caused by endogenous retroelements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18724932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Yan, N., Regalado-Magdos, A. D., Stiggelbout, B., Lee-Kirsch, M. A., Lieberman, J. <strong>The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1.</strong> Nature Immun. 11: 1005-1013, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20871604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20871604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20871604[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/ni.1941" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20871604">Yan et al. (2010)</a> observed enhanced Ifnb (<a href="/entry/147640">147640</a>) and Il6 (<a href="/entry/147620">147620</a>) expression in Trex1 -/- mouse embryonic fibroblasts (MEFs) infected with pseudotyped human immunodeficiency virus (HIV)-1 (see <a href="/entry/609423">609423</a>) compared with uninfected Trex1 -/- MEFs or infected wildtype MEFs. Ifnb induction was mediated by reverse transcribed HIV in an Irf3 (<a href="/entry/603734">603734</a>)-dependent manner. HIV reverse transcripts accumulated in Trex -/- MEFs. HIV-stimulated Ifnb from Trex1 -/- MEFs inhibited HIV. <a href="#26" class="mim-tip-reference" title="Yan, N., Regalado-Magdos, A. D., Stiggelbout, B., Lee-Kirsch, M. A., Lieberman, J. <strong>The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1.</strong> Nature Immun. 11: 1005-1013, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20871604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20871604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20871604[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/ni.1941" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20871604">Yan et al. (2010)</a> observed an increase in cytosolic HIV DNA and reduced viral spreading, accompanied by increased IFNA (<a href="/entry/147660">147660</a>) and IFNB expression, in human monocyte-derived macrophages treated with small interfering RNA (siRNA) against TREX1 and subsequently infected with HIV-1. Treatment of Trex1 -/- MEFs with siRNA against genes related to innate immunity showed that HIV DNA was detected by a pathway that signaled through Sting (TMEM173; <a href="/entry/612374">612374</a>), Tbk1 (<a href="/entry/604834">604834</a>), and Irf3 but not nucleic acid sensors. <a href="#26" class="mim-tip-reference" title="Yan, N., Regalado-Magdos, A. D., Stiggelbout, B., Lee-Kirsch, M. A., Lieberman, J. <strong>The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1.</strong> Nature Immun. 11: 1005-1013, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20871604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20871604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20871604[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/ni.1941" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20871604">Yan et al. (2010)</a> proposed that HIV-1 uses TREX1 to avoid triggering antiviral innate immunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20871604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using mutation analysis with recombinant human TREX1, <a href="#6" class="mim-tip-reference" title="Fye, J. M., Orebaugh, C. D., Coffin, S. R., Hollis, T., Perrino, F. W. <strong>Dominant mutations of the TREX1 exonuclease gene in lupus and Aicardi-Goutieres syndrome.</strong> J. Biol. Chem. 286: 32373-32382, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21808053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21808053</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21808053[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.276287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21808053">Fye et al. (2011)</a> found that arg174 and lys175 within the flexible loop and arg128 in the catalytic core contributed to single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) degradation. TREX1 degraded endonuclease-treated hamster liver nuclei, suggesting that TREX1 contributes to apoptosis-associated DNA degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21808053" 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>Mutations in the TREX1 gene cause the type I IFN-associated autoimmune disease Aicardi-Goutieres syndrome (AGS1; <a href="/entry/225750">225750</a>). <a href="#1" class="mim-tip-reference" title="Ablasser, A., Hemmerling, I., Schmid-Burgk, J. L., Behrendt, R., Roers, A., Hornung, V. <strong>TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner.</strong> J. Immun. 192: 5993-5997, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24813208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24813208</a>] [<a href="https://doi.org/10.4049/jimmunol.1400737" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24813208">Ablasser et al. (2014)</a> found that knockout of the DNA sensor Cgas (MB21D1; <a href="/entry/613973">613973</a>) in Trex1-deficient mouse cells abrogated spontaneous induction of IFN-stimulated genes. They concluded that CGAS is a nonredundant sensor for endogenous DNA species and proposed that it may have value for the development of novel therapeutic approaches in sterile inflammatory conditions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24813208" 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 differentiating neural stem cells into astrocytes and treating them with short hairpin RNA (shRNAs) to AGS genes, <a href="#5" class="mim-tip-reference" title="Cuadrado, E., Michailidou, I., van Bodegraven, E. J., Jansen, M. H., Sluijs, J. A., Geerts, D., Couraud, P.-O., De Filippis, L., Vescovi, A. L., Kuijpers, T. W., Hol, E. M. <strong>Phenotypic variation in Aicardi-Goutieres syndrome explained by cell-specific IFN-stimulated gene response and cytokine release.</strong> J. Immun. 194: 3623-3633, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25769924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25769924</a>] [<a href="https://doi.org/10.4049/jimmunol.1401334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25769924">Cuadrado et al. (2015)</a> observed increased apoptosis in cells treated with shRNA to TREX1. Similarly, TREX1 silencing led to reduced proliferation of endothelial cells, but not of cells involved in angiogenesis. Silencing of TREX1 or SAMHD1 (<a href="/entry/606754">606754</a>), but not RNASEH2A (<a href="/entry/606034">606034</a>) or ADAR1 (<a href="/entry/146920">146920</a>), resulted in enhanced expression of IFN-stimulated genes (ISGs), such as IFIT1 (<a href="/entry/147690">147690</a>). TREX1 shRNA treatment led to increased production of proinflammatory and chemotactic cytokines. <a href="#5" class="mim-tip-reference" title="Cuadrado, E., Michailidou, I., van Bodegraven, E. J., Jansen, M. H., Sluijs, J. A., Geerts, D., Couraud, P.-O., De Filippis, L., Vescovi, A. L., Kuijpers, T. W., Hol, E. M. <strong>Phenotypic variation in Aicardi-Goutieres syndrome explained by cell-specific IFN-stimulated gene response and cytokine release.</strong> J. Immun. 194: 3623-3633, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25769924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25769924</a>] [<a href="https://doi.org/10.4049/jimmunol.1401334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25769924">Cuadrado et al. (2015)</a> proposed that activation of antiviral status in astrocytes and endothelial cells may lead to cerebral pathology and ultimately severe disease in AGS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25769924" 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="#15" class="mim-tip-reference" title="Maciejowski, J., Chatzipli, A., Dananberg, A., Chu, K., Toufektchan, E., Klimczak, L. J., Gordenin, D. A., Campbell, P. J., de Lange, T. <strong>APOBEC3-dependent kataegis and TREX1-driven chromothripsis during telomere crisis.</strong> Nature Genet. 52: 884-890, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32719516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32719516</a>] [<a href="https://doi.org/10.1038/s41588-020-0667-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32719516">Maciejowski et al. (2020)</a> examined the mechanism underlying chromothripsis and kataegis using an in vitro telomere crisis model in human cells and showed that the cytoplasmic exonuclease TREX1, which promotes resolution of dicentric chromosomes, played a prominent role in chromothriptic fragmentation. In the absence of TREX1, genome alterations induced by telomere crisis primarily involved breakage-fusion-bridge cycles and simple genome rearrangements rather than chromothripsis. Kataegis observed at chromothriptic breakpoints was due to cytosine deamination by APOBEC3B (<a href="/entry/607110">607110</a>). <a href="#15" class="mim-tip-reference" title="Maciejowski, J., Chatzipli, A., Dananberg, A., Chu, K., Toufektchan, E., Klimczak, L. J., Gordenin, D. A., Campbell, P. J., de Lange, T. <strong>APOBEC3-dependent kataegis and TREX1-driven chromothripsis during telomere crisis.</strong> Nature Genet. 52: 884-890, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32719516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32719516</a>] [<a href="https://doi.org/10.1038/s41588-020-0667-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32719516">Maciejowski et al. (2020)</a> concluded that chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32719516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Aicardi-Goutieres Syndrome 1</em></strong></p><p>
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In affected members of 10 families with Aicardi-Goutieres syndrome (AGS1; <a href="/entry/225750">225750</a>), <a href="#4" class="mim-tip-reference" title="Crow, Y. J., Hayward, B. E., Parmar, R., Robins, P., Leitch, A., Ali, M., Black, D. N., van Bokhoven, H., Brunner, H. G., Hamel, B. C., Corry, P. C., Cowan, F. M., and 14 others. <strong>Mutations in the gene encoding the 3-prime-5-prime DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus.</strong> Nature Genet. 38: 917-920, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16845398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16845398</a>] [<a href="https://doi.org/10.1038/ng1845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16845398">Crow et al. (2006)</a> identified 5 different mutations in the TREX1 gene in homozygous or compound heterozygous state (see, e.g., <a href="#0001">606609.0001</a>-<a href="#0004">606609.0004</a>). One of the mutations, R114H (<a href="#0001">606609.0001</a>), was identified in 7 European pedigrees. <a href="#4" class="mim-tip-reference" title="Crow, Y. J., Hayward, B. E., Parmar, R., Robins, P., Leitch, A., Ali, M., Black, D. N., van Bokhoven, H., Brunner, H. G., Hamel, B. C., Corry, P. C., Cowan, F. M., and 14 others. <strong>Mutations in the gene encoding the 3-prime-5-prime DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus.</strong> Nature Genet. 38: 917-920, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16845398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16845398</a>] [<a href="https://doi.org/10.1038/ng1845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16845398">Crow et al. (2006)</a> identified a homozygous mutation in the TREX1 gene (<a href="#0002">606609.0002</a>) in a patient originally diagnosed with Cree encephalitis, indicating that Cree encephalitis is the same disorder as AGS1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16845398" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Rice, G., Newman, W. G., Dean, J., Patrick, T., Parmar, R., Flintoff, K., Robins, P., Harvey, S., Hollis, T., O'Hara, A., Herrick, A. L., Bowden, A. P., Perrino, F. W., Lindahl, T., Barnes, D. E., Crow, Y. J. <strong>Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome.</strong> Am. J. Hum. Genet. 80: 811-815, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357087[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357087">Rice et al. (2007)</a> described a de novo heterozygous TREX1 mutation, affecting a critical catalytic residue in TREX1 (D200N; <a href="#0006">606609.0006</a>), that resulted in typical Aicardi-Goutieres syndrome, thus defining a dominant form of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17357087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Haaxma, C. A., Crow, Y. J., van Steensel, M. A. M., Lammens, M. M. Y., Rice, G. I., Verbeek, M. M., Willemsen, M. A. A. P. <strong>A de novo p.Asp18Asn mutation in TREX1 in a patient with Aicardi-Goutieres syndrome.</strong> Am. J. Med. Genet. 152A: 2612-2617, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20799324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20799324</a>] [<a href="https://doi.org/10.1002/ajmg.a.33620" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20799324">Haaxma et al. (2010)</a> reported a second patient with Aicardi-Goutieres syndrome and a de novo heterozygous TREX1 mutation (D18N; <a href="#0007">606609.0007</a>). The D18N mutation had previously been identified in heterozygosity by <a href="#11" class="mim-tip-reference" title="Lee-Kirsch, M. A., Chowdhury, D., Harvey, S., Gong, M., Senenko, L., Engel, K., Pfeiffer, C., Hollis, T., Gahr, M., Perrino, F. W., Lieberman, J., Hubner, N. <strong>A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus.</strong> J. Molec. Med. 85: 531-537, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17440703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17440703</a>] [<a href="https://doi.org/10.1007/s00109-007-0199-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17440703">Lee-Kirsch et al. (2007)</a> in a family with chilblain lupus. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20799324+17440703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Susceptibility to Systemic Lupus Erythematosus</em></strong></p><p>
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Aicardi-Goutieres syndrome shows overlap with systemic erythematosus (SLE; <a href="/entry/152700">152700</a>) at both clinical and pathologic levels. <a href="#12" class="mim-tip-reference" title="Lee-Kirsch, M. A., Gong, M., Chowdhury, D., Senenko, L., Engel, K., Lee, Y.-A., de Silva, U., Bailey, S. L., Witte, T., Vyse, T. J., Kere, J., Pfeiffer, C., and 12 others. <strong>Mutations in the gene encoding the 3-prime-5-prime DNA exonuclease TREX1 are associated with systemic lupus erythematosus.</strong> Nature Genet. 39: 1065-1067, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17660818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17660818</a>] [<a href="https://doi.org/10.1038/ng2091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17660818">Lee-Kirsch et al. (2007)</a> analyzed the TREX1 gene in 417 patients with SLE and 1,712 controls and identified heterozygosity for a 3-prime UTR variant and 11 nonsynonymous changes in 12 patients (see, e.g., <a href="#0001">606609.0001</a>). They found only 2 nonsynonymous changes in 2 controls (p = 1.7 X 10(-7), relative risk = 25.3). In vitro studies of 2 frameshift mutations revealed that both caused altered subcellular distribution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17660818" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Chilblain Lupus</em></strong></p><p>
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<a href="#20" class="mim-tip-reference" title="Rice, G., Newman, W. G., Dean, J., Patrick, T., Parmar, R., Flintoff, K., Robins, P., Harvey, S., Hollis, T., O'Hara, A., Herrick, A. L., Bowden, A. P., Perrino, F. W., Lindahl, T., Barnes, D. E., Crow, Y. J. <strong>Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome.</strong> Am. J. Hum. Genet. 80: 811-815, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357087[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357087">Rice et al. (2007)</a> reported a heterozygous TREX1 mutation (<a href="#0005">606609.0005</a>) causing familial chilblain lupus (CHBL; <a href="/entry/610448">610448</a>), a rare cutaneous form of SLE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17357087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of the large 5-generation German family with chilblain lupus in which the disease was mapped to chromosome 3p21-p14 by <a href="#13" class="mim-tip-reference" title="Lee-Kirsch, M. A., Gong, M., Schulz, H., Ruschendorf, F., Stein, A., Pfeiffer, C., Ballarini, A., Gahr, M., Hubner, N., Linne, M. <strong>Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p.</strong> Am. J. Hum. Genet. 79: 731-737, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16960810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16960810</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16960810[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/507848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16960810">Lee-Kirsch et al. (2006)</a>, <a href="#11" class="mim-tip-reference" title="Lee-Kirsch, M. A., Chowdhury, D., Harvey, S., Gong, M., Senenko, L., Engel, K., Pfeiffer, C., Hollis, T., Gahr, M., Perrino, F. W., Lieberman, J., Hubner, N. <strong>A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus.</strong> J. Molec. Med. 85: 531-537, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17440703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17440703</a>] [<a href="https://doi.org/10.1007/s00109-007-0199-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17440703">Lee-Kirsch et al. (2007)</a> identified heterozygosity for a missense mutation (D18N; <a href="#0007">606609.0007</a>) in the TREX1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16960810+17440703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations</em></strong></p><p>
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In 9 families with autosomal dominant retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS; <a href="/entry/192315">192315</a>), <a href="#22" class="mim-tip-reference" title="Richards, A., van den Maagdenberg, A. M. J. M., Jen, J. C., Kavanagh, D., Bertram, P., Spitzer, D., Liszewski, M. K., Barilla-LaBarca, M.-L., Terwindt, G. M., Kasai, Y., McLellan, M., Grand, M. G., and 25 others. <strong>C-terminal truncations in human 3-prime-5-prime DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.</strong> Nature Genet. 39: 1068-1070, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17660820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17660820</a>] [<a href="https://doi.org/10.1038/ng2082" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17660820">Richards et al. (2007)</a> identified 5 different heterozygous frameshift mutations at the C terminus of the TREX1 gene (see, e.g., <a href="#0008">606609.0008</a> and <a href="#0009">606609.0009</a>). In expression studies, the truncated proteins retained exonuclease activity but lost normal perinuclear localization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17660820" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The TREX1 D200N and D18N dominant heterozygous mutations are associated with AGS1 and CHBL, respectively. Using exonuclease enzyme analysis, <a href="#14" class="mim-tip-reference" title="Lehtinen, D. A., Harvey, S., Mulcahy, M. J., Hollis, T., Perrino, F. W. <strong>The TREX1 double-stranded DNA degradation activity is defective in dominant mutations associated with autoimmune disease.</strong> J. Biol. Chem. 283: 31649-31656, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18805785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18805785</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18805785[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M806155200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18805785">Lehtinen et al. (2008)</a> showed that TREX1 heterodimers containing wildtype TREX1 and either D200N or D18N mutant proteins were completely deficient in degrading dsDNA and degraded ssDNA at an approximately 2-fold lower rate than wildtype TREX1. In addition, D200N- and D18N-containing homo- and heterodimers inhibited the dsDNA degradation activity of wildtype TREX1, providing an explanation for the dominant phenotype of the mutant alleles. In contrast, the R114H mutation, which causes AGS1 when present as a homozygous mutation and SLE when present as a heterozygous mutation, had dysfunctional dsDNA and ssDNA degradation activities as a homodimer, but it was functional as a heterodimer. The R114H homodimer lacked inhibitory activity against wildtype TREX1, supporting the recessive genetics of the R114H mutation in AGS1. <a href="#14" class="mim-tip-reference" title="Lehtinen, D. A., Harvey, S., Mulcahy, M. J., Hollis, T., Perrino, F. W. <strong>The TREX1 double-stranded DNA degradation activity is defective in dominant mutations associated with autoimmune disease.</strong> J. Biol. Chem. 283: 31649-31656, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18805785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18805785</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18805785[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M806155200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18805785">Lehtinen et al. (2008)</a> concluded that the dysfunctional dsDNA activities of the disease-related TREX1 mutants could account for persistent dsDNA from dying cells leading to an aberrant autoimmune response in these disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18805785" 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="#18" class="mim-tip-reference" title="Morita, M., Stamp, G., Robins, P., Dulic, A., Rosewell, I., Hrivnak, G., Daly, G., Lindahl, T., Barnes, D. E. <strong>Gene-targeted mice lacking the Trex1 (DNase III) 3-prime to 5-prime DNA exonuclease develop inflammatory myocarditis.</strong> Molec. Cell. Biol. 24: 6719-6727, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15254239/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15254239</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15254239[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.24.15.6719-6727.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15254239">Morita et al. (2004)</a> found that Trex1 -/- mice developed inflammatory myocarditis, suggesting a role for this enzyme in immune regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15254239" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Peschke, K., Achleitner, M., Frenzel, K., Gerbaulet, A., Ada, S. R., Zeller, N., Lienenklaus, S., Lesche, M., Poulet, C., Naumann, R., Dahl, A., Ravens, U., Gunther, C., Muller, W., Knobleloch, K.-P., Prinz, M., Roers, A., Behrendt, R. <strong>Loss of Trex1 in dendritic cells is sufficient to trigger systemic autoimmunity.</strong> J. Immun. 197: 2157-2166, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27511730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27511730</a>] [<a href="https://doi.org/10.4049/jimmunol.1600722" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27511730">Peschke et al. (2016)</a> found that mice with conditional loss of Trex1 in dendritic cells had increased Ifn-inducible gene expression (e.g., IFI44; <a href="/entry/610468">610468</a>) and autoimmunity, as assessed by histologic analysis. Loss of Trex1 in keratinocytes or microglia resulted in Ifn production but did not induce inflammation. Inactivation of Trex1 in B cells, cardiomyocytes, neurons, or astrocytes did not produce detectable responses. <a href="#19" class="mim-tip-reference" title="Peschke, K., Achleitner, M., Frenzel, K., Gerbaulet, A., Ada, S. R., Zeller, N., Lienenklaus, S., Lesche, M., Poulet, C., Naumann, R., Dahl, A., Ravens, U., Gunther, C., Muller, W., Knobleloch, K.-P., Prinz, M., Roers, A., Behrendt, R. <strong>Loss of Trex1 in dendritic cells is sufficient to trigger systemic autoimmunity.</strong> J. Immun. 197: 2157-2166, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27511730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27511730</a>] [<a href="https://doi.org/10.4049/jimmunol.1600722" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27511730">Peschke et al. (2016)</a> concluded that TREX1 expression in dendritic cells is essential to prevent loss of self-tolerance resulting from aberrant detection of endogenous DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27511730" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Simpson, S. R., Rego, S. L., Harvey, S. E., Liu, M., Hemphill, W. O., Venkatadri, R., Sharma, R., Grayson, J. M., Perrino, F. W. <strong>T cells produce IFN-alpha in the TREX1 D18N model of lupus-like autoimmunity.</strong> J. Immun. 204: 348-359, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31826941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31826941</a>] [<a href="https://doi.org/10.4049/jimmunol.1900220" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31826941">Simpson et al. (2020)</a> found that mice expressing the catalytically inactive D18N Trex1 mutation developed lupus-like autoimmunity associated with self-DNA sensing and abnormal expression of IFN-alpha and -beta in T cells. Trex1 inactivation resulted in activated T cells that constitutively expressed all molecular components of the DNA sensing and signaling pathways required for cytosolic DNA detection and IFN-alpha/beta production, leading to abnormal production of type I IFN in T cells and, consequently, autoimmunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31826941" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=606609[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> rs72556554 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72556554;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/rs72556554?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=rs72556554" 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=rs72556554" 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=RCV000004396 OR RCV000004397 OR RCV000256102 OR RCV000850611 OR RCV001266495 OR RCV002281693 OR RCV004540989 OR RCV005025005" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004396, RCV000004397, RCV000256102, RCV000850611, RCV001266495, RCV002281693, RCV004540989, RCV005025005" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004396...</a>
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In affected members of 7 families of European origin with Aicardi-Goutieres syndrome-1 (AGS1; <a href="/entry/225750">225750</a>), <a href="#4" class="mim-tip-reference" title="Crow, Y. J., Hayward, B. E., Parmar, R., Robins, P., Leitch, A., Ali, M., Black, D. N., van Bokhoven, H., Brunner, H. G., Hamel, B. C., Corry, P. C., Cowan, F. M., and 14 others. <strong>Mutations in the gene encoding the 3-prime-5-prime DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus.</strong> Nature Genet. 38: 917-920, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16845398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16845398</a>] [<a href="https://doi.org/10.1038/ng1845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16845398">Crow et al. (2006)</a> identified a 341G-A transition in the TREX1 gene, resulting in an arg114-to-his (R114H) substitution at a residue predicted to be involved in protein dimerization. Five of the families were homozygous for the mutation and 2 were compound heterozygous with another TREX1 mutation (<a href="#0003">606609.0003</a>). Patient-derived fibroblasts showed no detectable TREX1 3-prime exonuclease activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16845398" 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 an extensive study of the clinical and molecular phenotypes of Aicardi-Goutieres syndrome, <a href="#21" class="mim-tip-reference" title="Rice, G., Patrick, T., Parmar, R., Taylor, C. F., Aeby, A., Aicardi, J., Artuch, R., Montalto, S. A., Bacino, C. A., Barroso, B., Baxter, P., Benko, W. S., and 106 others. <strong>Clinical and molecular phenotype of Aicardi-Goutieres syndrome.</strong> Am. J. Hum. Genet. 81: 713-725, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17846997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17846997</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17846997[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/521373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17846997">Rice et al. (2007)</a> found biallelic mutations in TREX1 in 31 of 127 families with the clinical diagnosis of the disorder. Eighteen families, 14 of which were of northern European origin, were homozygous (15) or compound heterozygous (3) for the 341G-A transition (R114H). Notably, all R114H homozygotes were also homozygous for the T allele of a SNP at position 531. This allele exhibited highly significant (P less than 0.001) overrepresentation in patients compared with controls (with a T allele population frequency of 0.4), suggesting that R114H might be an ancient founder mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17846997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Systemic Lupus Erythematosus, Susceptibility to</em></strong></p><p>
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<a href="#12" class="mim-tip-reference" title="Lee-Kirsch, M. A., Gong, M., Chowdhury, D., Senenko, L., Engel, K., Lee, Y.-A., de Silva, U., Bailey, S. L., Witte, T., Vyse, T. J., Kere, J., Pfeiffer, C., and 12 others. <strong>Mutations in the gene encoding the 3-prime-5-prime DNA exonuclease TREX1 are associated with systemic lupus erythematosus.</strong> Nature Genet. 39: 1065-1067, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17660818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17660818</a>] [<a href="https://doi.org/10.1038/ng2091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17660818">Lee-Kirsch et al. (2007)</a> analyzed the TREX1 gene in 417 patients with systemic lupus erythematosus (<a href="/entry/152700">152700</a>) and identified heterozygosity for the R114H mutation in a European female patient who had nephritis, arthritis, and antinuclear and anti-dsDNA antibodies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17660818" 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">rs78218009 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs78218009;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=rs78218009" 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=rs78218009" 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=RCV000004398 OR RCV000378411 OR RCV001384591 OR RCV004532286" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004398, RCV000378411, RCV001384591, RCV004532286" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004398...</a>
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<p>In a patient with Cree encephalitis, also known as Aicardi-Goutieres syndrome-1 (AGS1; <a href="/entry/225750">225750</a>), who was born of consanguineous parents, <a href="#4" class="mim-tip-reference" title="Crow, Y. J., Hayward, B. E., Parmar, R., Robins, P., Leitch, A., Ali, M., Black, D. N., van Bokhoven, H., Brunner, H. G., Hamel, B. C., Corry, P. C., Cowan, F. M., and 14 others. <strong>Mutations in the gene encoding the 3-prime-5-prime DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus.</strong> Nature Genet. 38: 917-920, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16845398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16845398</a>] [<a href="https://doi.org/10.1038/ng1845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16845398">Crow et al. (2006)</a> identified a homozygous 490C-T transition in the TREX1 gene, resulting in an arg164-to-ter (R164X) substitution. A lymphoblastoid cell line derived from the patient showed no detectable 3-prime exonuclease activity. The findings confirmed that Cree encephalitis and AGS1 are the same disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16845398" 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">rs74556809 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74556809;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=rs74556809" 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=rs74556809" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of 2 unrelated families with Aicardi-Goutieres syndrome (AGS1; <a href="/entry/225750">225750</a>), <a href="#4" class="mim-tip-reference" title="Crow, Y. J., Hayward, B. E., Parmar, R., Robins, P., Leitch, A., Ali, M., Black, D. N., van Bokhoven, H., Brunner, H. G., Hamel, B. C., Corry, P. C., Cowan, F. M., and 14 others. <strong>Mutations in the gene encoding the 3-prime-5-prime DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus.</strong> Nature Genet. 38: 917-920, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16845398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16845398</a>] [<a href="https://doi.org/10.1038/ng1845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16845398">Crow et al. (2006)</a> identified compound heterozygosity for 2 mutations in the TREX1 gene: a 3-bp insertion (600_601insGAT), resulting in duplication of an aspartate residue involved in divalent cation binding within the catalytic site, and R114H (<a href="#0001">606609.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16845398" 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">rs78408272 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs78408272;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=rs78408272" 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=rs78408272" 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 patient with Aicardi-Goutieres syndrome (AGS1; <a href="/entry/225750">225750</a>), who was born of consanguineous Turkish parents, <a href="#4" class="mim-tip-reference" title="Crow, Y. J., Hayward, B. E., Parmar, R., Robins, P., Leitch, A., Ali, M., Black, D. N., van Bokhoven, H., Brunner, H. G., Hamel, B. C., Corry, P. C., Cowan, F. M., and 14 others. <strong>Mutations in the gene encoding the 3-prime-5-prime DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus.</strong> Nature Genet. 38: 917-920, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16845398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16845398</a>] [<a href="https://doi.org/10.1038/ng1845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16845398">Crow et al. (2006)</a> identified a homozygous 602T-A transversion in the TREX1 gene, resulting in a val201-to-asp (V201D) substitution in the catalytic site of the protein. Patient-derived fibroblasts showed no detectable TREX1 3-prime exonuclease activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16845398" 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">rs1575292873 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1575292873;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=rs1575292873" 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=rs1575292873" 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=RCV001804149 OR RCV004719620 OR RCV005031387" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001804149, RCV004719620, RCV005031387" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001804149...</a>
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<p>In a nonconsanguineous Bangladeshi family, <a href="#20" class="mim-tip-reference" title="Rice, G., Newman, W. G., Dean, J., Patrick, T., Parmar, R., Flintoff, K., Robins, P., Harvey, S., Hollis, T., O'Hara, A., Herrick, A. L., Bowden, A. P., Perrino, F. W., Lindahl, T., Barnes, D. E., Crow, Y. J. <strong>Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome.</strong> Am. J. Hum. Genet. 80: 811-815, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357087[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357087">Rice et al. (2007)</a> found association between chilblain lupus (CHBL1; <a href="/entry/610448">610448</a>) and a heterozygous mutation in the TREX1 gene, the duplication of a single base (375dupT) that resulted in a truncated protein missing the last 188 amino acids. The mutation was present in 3 affected sibs; it was found also in a fourth sib with a subclinical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17357087" 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">rs78846775 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs78846775;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=rs78846775" 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=rs78846775" 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=RCV000004402 OR RCV000114331 OR RCV002512754" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004402, RCV000114331, RCV002512754" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004402...</a>
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<p>In a child with a classic history of Aicardi-Goutieres syndrome (AGS1; <a href="/entry/225750">225750</a>), who was born to nonconsanguineous Scottish parents, <a href="#20" class="mim-tip-reference" title="Rice, G., Newman, W. G., Dean, J., Patrick, T., Parmar, R., Flintoff, K., Robins, P., Harvey, S., Hollis, T., O'Hara, A., Herrick, A. L., Bowden, A. P., Perrino, F. W., Lindahl, T., Barnes, D. E., Crow, Y. J. <strong>Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome.</strong> Am. J. Hum. Genet. 80: 811-815, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357087[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357087">Rice et al. (2007)</a> found heterozygosity for a missense mutation in the TREX1 gene: a 598G-A transition that resulted in a substitution of asparagine for aspartic acid at codon 200 (D200N). Both parents had a homozygous wildtype genotype at this position, suggesting a de novo occurrence. Differentiation of the maternal and paternal alleles was possible because of a frequently observed C-to-T SNP at position 531, which allowed the authors to demonstrate that the mutation has arisen on the maternal allele. A standard exonuclease assay indicated close-to-normal TREX1 enzymatic activity. <a href="#20" class="mim-tip-reference" title="Rice, G., Newman, W. G., Dean, J., Patrick, T., Parmar, R., Flintoff, K., Robins, P., Harvey, S., Hollis, T., O'Hara, A., Herrick, A. L., Bowden, A. P., Perrino, F. W., Lindahl, T., Barnes, D. E., Crow, Y. J. <strong>Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome.</strong> Am. J. Hum. Genet. 80: 811-815, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357087[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357087">Rice et al. (2007)</a> hypothesized that the aspartic acid at position 200 of TREX1 represents one of 4 residues essential for coordinating 2 magnesium ions involved in DNA binding and catalysis, and that the D200N mutation represents a gain-of-function mutation conferring altered substrate specificity, DNA binding, or protein-protein interaction which would not be detected in a standard TREX1 exonuclease assay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17357087" 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="Fye, J. M., Orebaugh, C. D., Coffin, S. R., Hollis, T., Perrino, F. W. <strong>Dominant mutations of the TREX1 exonuclease gene in lupus and Aicardi-Goutieres syndrome.</strong> J. Biol. Chem. 286: 32373-32382, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21808053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21808053</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21808053[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.276287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21808053">Fye et al. (2011)</a> stated that asp18 and asp200 are the 2 aspartates that coordinate the divalent metal ion Mg(2+) at the TREX1 active site and contribute to DNA binding and catalysis. They found that homodimers of recombinant human TREX1 containing D200N or D18N (<a href="#0007">606609.0007</a>) mutations had negligible nuclease activity against ssDNA and dsDNA compared with wildtype. Heterodimers of wildtype TREX1 with D18N or D200N TREX1 mutants had more modestly reduced ssDNA nuclease activity, but profoundly reduced dsDNA nuclease activity, compared with wildtype homodimers. <a href="#6" class="mim-tip-reference" title="Fye, J. M., Orebaugh, C. D., Coffin, S. R., Hollis, T., Perrino, F. W. <strong>Dominant mutations of the TREX1 exonuclease gene in lupus and Aicardi-Goutieres syndrome.</strong> J. Biol. Chem. 286: 32373-32382, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21808053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21808053</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21808053[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.276287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21808053">Fye et al. (2011)</a> concluded that the dominant phenotypes of asp18 and asp200 mutations relate predominantly to impaired dsDNA degradation and indicate that TREX1 dsDNA degradation activity is fundamental to the prevention of autoimmunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21808053" 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">rs121908117 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908117;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=rs121908117" 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=rs121908117" 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=RCV000004405 OR RCV000114329 OR RCV000323773 OR RCV000819829 OR RCV001804150" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004405, RCV000114329, RCV000323773, RCV000819829, RCV001804150" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004405...</a>
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<p><strong><em>Chilblain Lupus</em></strong></p><p>
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In affected members of the large 5-generation German family with chilblain lupus (CHBL1; <a href="/entry/610448">610448</a>) described by <a href="#13" class="mim-tip-reference" title="Lee-Kirsch, M. A., Gong, M., Schulz, H., Ruschendorf, F., Stein, A., Pfeiffer, C., Ballarini, A., Gahr, M., Hubner, N., Linne, M. <strong>Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p.</strong> Am. J. Hum. Genet. 79: 731-737, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16960810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16960810</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16960810[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/507848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16960810">Lee-Kirsch et al. (2006)</a>, <a href="#11" class="mim-tip-reference" title="Lee-Kirsch, M. A., Chowdhury, D., Harvey, S., Gong, M., Senenko, L., Engel, K., Pfeiffer, C., Hollis, T., Gahr, M., Perrino, F. W., Lieberman, J., Hubner, N. <strong>A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus.</strong> J. Molec. Med. 85: 531-537, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17440703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17440703</a>] [<a href="https://doi.org/10.1007/s00109-007-0199-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17440703">Lee-Kirsch et al. (2007)</a> identified heterozygosity for a 52G-A transition in exon 1 of the TREX1 gene, resulting in an asp18-to-asn (D18N) substitution at a highly conserved residue critical for catalytic activity. The mutation was not found in unaffected family members or in 400 control chromosomes. Recombinant mutant TREX1 homodimers were enzymatically inactive, whereas mutant/wildtype heterodimers had approximately 40% of the activity of wildtype dimers, indicating that D18N is a loss-of-function allele that does not exhibit a dominant-negative effect. Compared to control cells, patient-derived lymphoblastoid cells were substantially less sensitive to cell death after treatment with granzyme A (GZMA; <a href="/entry/140050">140050</a>) but not granzyme B (GZMB; <a href="/entry/123910">123910</a>), indicating that D18N specifically interferes with GZMA-mediated cell death in the caspase-independent form of apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16960810+17440703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Aicardi-Goutieres Syndrome 1</em></strong></p><p>
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In a 16-year-old girl with relatively mild Aicardi-Goutieres syndrome (AGS1; <a href="/entry/225750">225750</a>), who was negative for mutation in other known AGS genes, <a href="#8" class="mim-tip-reference" title="Haaxma, C. A., Crow, Y. J., van Steensel, M. A. M., Lammens, M. M. Y., Rice, G. I., Verbeek, M. M., Willemsen, M. A. A. P. <strong>A de novo p.Asp18Asn mutation in TREX1 in a patient with Aicardi-Goutieres syndrome.</strong> Am. J. Med. Genet. 152A: 2612-2617, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20799324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20799324</a>] [<a href="https://doi.org/10.1002/ajmg.a.33620" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20799324">Haaxma et al. (2010)</a> identified a de novo heterozygous D18N missense mutation in the TREX1 gene. The mutation was not found in either parent or in 200 control chromosomes. The patient also displayed features of mitochondrial disease, with cytochrome oxidase-negative and ragged-red fibers seen on histologic examination of the quadriceps muscle; biochemical measurements showed decreased overall energy production (ATP and CrP) in the presence of normal activities of individual respiratory chain complexes, again compatible with mitochondrial dysfunction. However, heteroduplex analysis of the entire mitochondrial DNA did not show any mutations. This patient also had peripheral neuropathy with prominent axonal loss and disturbances of myelination without strict demyelination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20799324" 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="Fye, J. M., Orebaugh, C. D., Coffin, S. R., Hollis, T., Perrino, F. W. <strong>Dominant mutations of the TREX1 exonuclease gene in lupus and Aicardi-Goutieres syndrome.</strong> J. Biol. Chem. 286: 32373-32382, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21808053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21808053</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21808053[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.276287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21808053">Fye et al. (2011)</a> stated that asp18 and asp200 are the 2 aspartates that coordinate the divalent metal ion Mg(2+) at the TREX1 active site and contribute to DNA binding and catalysis. They found that homodimers of recombinant human TREX1 containing D200N (<a href="#0006">606609.0006</a>) or D18N mutations had negligible nuclease activity against ssDNA and dsDNA compared with wildtype. Heterodimers of wildtype TREX1 with D18N or D200N TREX1 mutants had more modestly reduced ssDNA nuclease activity, but profoundly reduced dsDNA nuclease activity, compared with wildtype homodimers. <a href="#6" class="mim-tip-reference" title="Fye, J. M., Orebaugh, C. D., Coffin, S. R., Hollis, T., Perrino, F. W. <strong>Dominant mutations of the TREX1 exonuclease gene in lupus and Aicardi-Goutieres syndrome.</strong> J. Biol. Chem. 286: 32373-32382, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21808053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21808053</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21808053[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.276287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21808053">Fye et al. (2011)</a> concluded that the dominant phenotypes of asp18 and asp200 mutations relates predominantly to impaired dsDNA degradation and indicates that TREX1 dsDNA degradation activity is fundamental to the prevention of autoimmunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21808053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 VASCULOPATHY, RETINAL, WITH CEREBRAL LEUKOENCEPHALOPATHY AND SYSTEMIC MANIFESTATIONS</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">rs1553820434 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553820434;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=rs1553820434" 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=rs1553820434" 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=RCV000004403 OR RCV000519088 OR RCV000795266" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004403, RCV000519088, RCV000795266" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004403...</a>
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<p>In 5 families with autosomal dominant retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS; <a href="/entry/192315">192315</a>), including 2 North American families previously reported by <a href="#7" class="mim-tip-reference" title="Grand, M. G., Kaine, J., Fulling, K., Atkinson, J., Dowton, S. B., Farber, M., Craver, J., Rice, K. <strong>Cerebroretinal vasculopathy.</strong> Ophthalmology 95: 649-659, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3174024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3174024</a>] [<a href="https://doi.org/10.1016/s0161-6420(88)33131-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3174024">Grand et al. (1988)</a> and 1 Dutch pedigree originally described by <a href="#25" class="mim-tip-reference" title="Storimans, C. W., Van Schooneveld, M. J., Oosterhuis, J. A., Bos, P. J. <strong>A new autosomal dominant vascular retinopathy syndrome.</strong> Europ. J. Ophthal. 1: 73-78, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1821204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1821204</a>] [<a href="https://doi.org/10.1177/112067219100100204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1821204">Storimans et al. (1991)</a>, <a href="#22" class="mim-tip-reference" title="Richards, A., van den Maagdenberg, A. M. J. M., Jen, J. C., Kavanagh, D., Bertram, P., Spitzer, D., Liszewski, M. K., Barilla-LaBarca, M.-L., Terwindt, G. M., Kasai, Y., McLellan, M., Grand, M. G., and 25 others. <strong>C-terminal truncations in human 3-prime-5-prime DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.</strong> Nature Genet. 39: 1068-1070, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17660820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17660820</a>] [<a href="https://doi.org/10.1038/ng2082" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17660820">Richards et al. (2007)</a> identified heterozygosity for a 1-bp insertion (3688G) at the C terminus of the TREX1 gene, resulting in a frameshift at val235 (V235fs). Haplotype analysis suggested that these families were not related. The mutation was not found in 192 Caucasian, 192 Chinese, or 300 Dutch control alleles. In expression studies, the truncated protein retained exonuclease activity but lost normal perinuclear localization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3174024+17660820+1821204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 VASCULOPATHY, RETINAL, WITH CEREBRAL LEUKOENCEPHALOPATHY AND SYSTEMIC MANIFESTATIONS</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">rs1560113283 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1560113283;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=rs1560113283" 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=rs1560113283" 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=RCV000004406" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004406" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004406</a>
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<p>In a North American family of Chinese ancestry with autosomal dominant retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS; <a href="/entry/192315">192315</a>), previously reported by <a href="#10" class="mim-tip-reference" title="Jen, J., Cohen, A. H., Yue, Q., Stout, J. T., Vinters, H. V., Nelson, S., Baloh, R. W. <strong>Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS).</strong> Neurology 49: 1322-1330, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9371916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9371916</a>] [<a href="https://doi.org/10.1212/wnl.49.5.1322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9371916">Jen et al. (1997)</a>, <a href="#22" class="mim-tip-reference" title="Richards, A., van den Maagdenberg, A. M. J. M., Jen, J. C., Kavanagh, D., Bertram, P., Spitzer, D., Liszewski, M. K., Barilla-LaBarca, M.-L., Terwindt, G. M., Kasai, Y., McLellan, M., Grand, M. G., and 25 others. <strong>C-terminal truncations in human 3-prime-5-prime DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.</strong> Nature Genet. 39: 1068-1070, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17660820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17660820</a>] [<a href="https://doi.org/10.1038/ng2082" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17660820">Richards et al. (2007)</a> identified heterozygosity for a 4-bp duplication (3727dupGTCA) at the C terminus of the TREX1 gene, resulting in a frameshift at thr249 (T249fs). The mutation was not found in 192 Caucasian, 192 Chinese, or 300 Dutch control alleles. In expression studies, the truncated protein retained exonuclease activity but lost normal perinuclear localization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9371916+17660820" 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> rs72556554 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72556554;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/rs72556554?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=rs72556554" 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=rs72556554" 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=RCV000004396 OR RCV000004397 OR RCV000256102 OR RCV000850611 OR RCV001266495 OR RCV002281693 OR RCV004540989 OR RCV005025005" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004396, RCV000004397, RCV000256102, RCV000850611, RCV001266495, RCV002281693, RCV004540989, RCV005025005" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004396...</a>
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<p>In a 2-month-old boy (patient 4) with Aicardi-Goutieres syndrome (AGS1; <a href="/entry/225750">225750</a>), <a href="#2" class="mim-tip-reference" title="Adang, L. A., Frank, D. B., Gilani, A., Takanohashi, A., Ulrick, N., Collins, A., Cross, Z., Galambos, C., Helman, G., Kanaan, U., Keller, S., Simon, D., Sherbini, O., Hanna, B. D., Vanderver, A. L. <strong>Aicardi Goutieres syndrome is associated with pulmonary hypertension.</strong> Molec. Genet. Metab. 125: 351-358, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30219631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30219631</a>] [<a href="https://doi.org/10.1016/j.ymgme.2018.09.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30219631">Adang et al. (2018)</a> identified compound heterozygous mutations in the TREX1 gene: a c.506G-A transition, resulting in an arg169-to-his (R169H) substitution, and a 1-bp deletion (c.581delC), resulting in frameshift (Arg194fs). The patient presented with pulmonary hypertension that ultimately caused his death at 12 weeks of age. He also had CNS perivascular calcifications and gastrointestinal symptoms, but no dermatologic manifestations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30219631" 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>.0011 AICARDI-GOUTIERES SYNDROME 1</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">rs1575293518 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1575293518;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=rs1575293518" 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=rs1575293518" 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=RCV000754080" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000754080" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000754080</a>
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<p>For discussion of the 1-bp deletion (c.581delC) in the TREX1 gene that was found in compound heterozygous state in a patient with Aicardi-Goutieres syndrome (AGS1; <a href="/entry/225750">225750</a>) by <a href="#2" class="mim-tip-reference" title="Adang, L. A., Frank, D. B., Gilani, A., Takanohashi, A., Ulrick, N., Collins, A., Cross, Z., Galambos, C., Helman, G., Kanaan, U., Keller, S., Simon, D., Sherbini, O., Hanna, B. D., Vanderver, A. L. <strong>Aicardi Goutieres syndrome is associated with pulmonary hypertension.</strong> Molec. Genet. Metab. 125: 351-358, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30219631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30219631</a>] [<a href="https://doi.org/10.1016/j.ymgme.2018.09.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30219631">Adang et al. (2018)</a>, see <a href="#0010">606609.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30219631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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Ablasser, A., Hemmerling, I., Schmid-Burgk, J. L., Behrendt, R., Roers, A., Hornung, V.
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<strong>TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner.</strong>
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J. Immun. 192: 5993-5997, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24813208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24813208</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24813208" 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/10.4049/jimmunol.1400737" target="_blank">Full Text</a>]
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Adang, L. A., Frank, D. B., Gilani, A., Takanohashi, A., Ulrick, N., Collins, A., Cross, Z., Galambos, C., Helman, G., Kanaan, U., Keller, S., Simon, D., Sherbini, O., Hanna, B. D., Vanderver, A. L.
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<strong>Aicardi Goutieres syndrome is associated with pulmonary hypertension.</strong>
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Molec. Genet. Metab. 125: 351-358, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30219631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30219631</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30219631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2018.09.004" target="_blank">Full Text</a>]
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Chowdhury, D., Beresford, P. J., Zhu, P., Zhang, D., Sung, J.-S., Demple, B., Perrino, F. W., Lieberman, J.
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<strong>The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death.</strong>
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Molec. Cell 23: 133-142, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16818237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16818237</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16818237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2006.06.005" target="_blank">Full Text</a>]
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Crow, Y. J., Hayward, B. E., Parmar, R., Robins, P., Leitch, A., Ali, M., Black, D. N., van Bokhoven, H., Brunner, H. G., Hamel, B. C., Corry, P. C., Cowan, F. M., and 14 others.
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<strong>Mutations in the gene encoding the 3-prime-5-prime DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus.</strong>
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Nature Genet. 38: 917-920, 2006.
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Rice, G., Newman, W. G., Dean, J., Patrick, T., Parmar, R., Flintoff, K., Robins, P., Harvey, S., Hollis, T., O'Hara, A., Herrick, A. L., Bowden, A. P., Perrino, F. W., Lindahl, T., Barnes, D. E., Crow, Y. J.
|
|
<strong>Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome.</strong>
|
|
Am. J. Hum. Genet. 80: 811-815, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357087[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=17357087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/513443" 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="21" class="mim-anchor"></a>
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<a id="Rice2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rice, G., Patrick, T., Parmar, R., Taylor, C. F., Aeby, A., Aicardi, J., Artuch, R., Montalto, S. A., Bacino, C. A., Barroso, B., Baxter, P., Benko, W. S., and 106 others.
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<strong>Clinical and molecular phenotype of Aicardi-Goutieres syndrome.</strong>
|
|
Am. J. Hum. Genet. 81: 713-725, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17846997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17846997</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17846997[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=17846997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/521373" 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="22" class="mim-anchor"></a>
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<a id="Richards2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Richards, A., van den Maagdenberg, A. M. J. M., Jen, J. C., Kavanagh, D., Bertram, P., Spitzer, D., Liszewski, M. K., Barilla-LaBarca, M.-L., Terwindt, G. M., Kasai, Y., McLellan, M., Grand, M. G., and 25 others.
|
|
<strong>C-terminal truncations in human 3-prime-5-prime DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.</strong>
|
|
Nature Genet. 39: 1068-1070, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17660820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17660820</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17660820" 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/ng2082" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Simpson2020" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Simpson, S. R., Rego, S. L., Harvey, S. E., Liu, M., Hemphill, W. O., Venkatadri, R., Sharma, R., Grayson, J. M., Perrino, F. W.
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<strong>T cells produce IFN-alpha in the TREX1 D18N model of lupus-like autoimmunity.</strong>
|
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J. Immun. 204: 348-359, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31826941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31826941</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31826941" 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/10.4049/jimmunol.1900220" 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="24" class="mim-anchor"></a>
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<a id="Stetson2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stetson, D. B., Ko, J. S., Heidmann, T., Medzhitov, R.
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<strong>Trex1 prevents cell-intrinsic initiation of autoimmunity.</strong>
|
|
Cell 134: 587-598, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18724932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18724932</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18724932[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=18724932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.cell.2008.06.032" 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="25" class="mim-anchor"></a>
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<a id="Storimans1991" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Storimans, C. W., Van Schooneveld, M. J., Oosterhuis, J. A., Bos, P. J.
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<strong>A new autosomal dominant vascular retinopathy syndrome.</strong>
|
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Europ. J. Ophthal. 1: 73-78, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1821204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1821204</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1821204" 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/10.1177/112067219100100204" 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="26" class="mim-anchor"></a>
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<a id="Yan2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yan, N., Regalado-Magdos, A. D., Stiggelbout, B., Lee-Kirsch, M. A., Lieberman, J.
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<strong>The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1.</strong>
|
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Nature Immun. 11: 1005-1013, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20871604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20871604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20871604[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=20871604" 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/ni.1941" target="_blank">Full Text</a>]
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</p>
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</div>
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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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Ada Hamosh - updated : 01/21/2021
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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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Bao Lige - updated : 05/04/2020<br>Ada Hamosh - updated : 01/17/2019<br>Paul J. Converse - updated : 01/11/2017<br>Paul J. Converse - updated : 12/18/2015<br>Paul J. Converse - updated : 10/2/2015<br>Paul J. Converse - updated : 4/24/2015<br>Patricia A. Hartz - updated : 3/21/2012<br>Marla J. F. O'Neill - updated : 12/16/2010<br>Paul J. Converse - updated : 2/27/2009<br>Paul J. Converse - updated : 11/20/2008<br>Victor A. McKusick - updated : 10/3/2007<br>Marla J. F. O'Neill - updated : 9/20/2007<br>Marla J. F. O'Neill - updated : 8/30/2007
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</span>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse : 1/14/2002
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</span>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/25/2021
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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 : 01/22/2021<br>mgross : 01/21/2021<br>mgross : 05/04/2020<br>carol : 01/22/2019<br>carol : 01/18/2019<br>alopez : 01/17/2019<br>carol : 10/18/2017<br>carol : 04/28/2017<br>mgross : 01/11/2017<br>mgross : 12/18/2015<br>alopez : 10/21/2015<br>mgross : 10/5/2015<br>mgross : 10/2/2015<br>mgross : 10/2/2015<br>mgross : 10/2/2015<br>mgross : 4/24/2015<br>joanna : 3/20/2015<br>mgross : 5/24/2012<br>mgross : 5/24/2012<br>terry : 3/21/2012<br>carol : 1/11/2012<br>alopez : 12/17/2010<br>terry : 12/16/2010<br>carol : 11/30/2010<br>wwang : 1/5/2010<br>ckniffin : 7/14/2009<br>mgross : 2/27/2009<br>terry : 2/27/2009<br>mgross : 12/2/2008<br>terry : 11/20/2008<br>wwang : 10/30/2007<br>alopez : 10/8/2007<br>terry : 10/3/2007<br>alopez : 9/20/2007<br>alopez : 9/20/2007<br>carol : 8/30/2007<br>terry : 8/30/2007<br>carol : 6/1/2007<br>alopez : 1/28/2002<br>mgross : 1/14/2002
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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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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 606609
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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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|
3-PRIME REPAIR EXONUCLEASE 1; TREX1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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DNase III
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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: TREX1</em></strong>
|
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 783787000;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
|
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<em>
|
|
Cytogenetic location: 3p21.31
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 3:48,465,830-48,467,645 </span>
|
|
</em>
|
|
</strong>
|
|
<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">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
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</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
3p21.31
|
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</span>
|
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</td>
|
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
{Systemic lupus erythematosus, susceptibility to}
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
152700
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
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</tr>
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|
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Aicardi-Goutieres syndrome 1, dominant and recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
225750
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
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</tr>
|
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Chilblain lupus
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
610448
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Vasculopathy, retinal, with cerebral leukoencephalopathy and systemic manifestations
|
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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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192315
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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 dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</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 multistep processes of DNA replication, repair, and recombination require the excision of nucleotides from DNA 3-prime termini. Enzymes containing 3-prime-to-5-prime exonuclease activity remove mismatched, modified, fragmented, and normal nucleotides to generate the appropriate 3-prime termini for subsequent steps in the DNA metabolic pathways (Mazur and Perrino, 1999). </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>By micropeptide sequence analysis of the 30-kD bovine Trex1 protein, PCR with degenerate primers, and EST database searching, Mazur and Perrino (1999) obtained cDNAs encoding mouse and human TREX1 and TREX2 (300370). Sequence analysis predicted that the 304-amino acid TREX1 protein is 44% identical to TREX2 (Mazur and Perrino (2001) corrected the TREX1 sequence to 314 amino acids). TREX1 contains 3 conserved exonuclease motifs, with an HxAxxD sequence in the third motif. Functional analysis confirmed that the 3-prime-to-5-prime exonuclease activity of the recombinant protein is comparable to that of the native protein and prefers mismatched 3-prime termini. Mazur and Perrino (1999) concluded that the TREX proteins are small, independent 3-prime excision enzymes, whereas the multifunctional p53 (191170) and WRN (RECQL2; 604611) proteins, which also have 3-prime-to-5-prime exonuclease activity, are much larger. </p><p>Using rabbit Trex1 to search an EST database, Hoss et al. (1999) also isolated human TREX1, which they termed DNase III. Northern blot analysis revealed expression of a 1.15-kb TREX1 transcript in all tissues tested. </p><p>Mazur and Perrino (2001) used 5-prime RACE to identify the flanking region of TREX1. Genomic sequence analysis suggested that TREX1 open reading frames are produced by a variety of mechanisms, including alternate promoter usage, alternative splicing, and varied sites for 3-prime cleavage. RT-PCR analysis detected ubiquitous expression of TREX1. </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>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>The TREX1 gene contains a single exon (Hoss et al., 1999; Mazur and Perrino, 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>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hoss et al. (1999) and Mazur and Perrino (2001) identified clones containing the TREX1 gene that map to chromosome 3p21.3-p21.2. </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>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">
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<p>SET (600960) and NM23H1 (NME1; 156490) reside in an endoplasmic reticulum-associated complex, the SET complex, that translocates to the nucleus in response to superoxide generation by granzyme A (GZMA; 140050). Chowdhury et al. (2006) identified TREX1 as a component of the SET complex. TREX1 bound SET and colocalized and translocated with the SET complex. On its own, TREX1 did not damage intact DNA, but it acted in concert with NM23H1 to destroy DNA during granzyme A-mediated cell death. After NM23H1 nicked 1 strand, TREX1 removed bases from the free 3-prime end to enhance the damage and prevent DNA end reannealing and repair. </p><p>Using mass spectrometry and Western blot analysis, Stetson et al. (2008) identified mouse Trex1 as a protein involved in recognition of interferon stimulatory DNA (ISD) BrdU-labeled intracellular oligonucleotides. Microarray analysis showed that Trex1 was upregulated in response to ISD stimulation. However, Trex1 -/- cells retained an intact ISD response, ruling out Trex1 as the ISD sensor. In contrast with Trex1 -/- mice, which succumb to lethal autoimmunity (see ANIMAL MODEL), Trex1 -/- mice lacking Irf3 (603734), Ifnar1 (107450), or Rag2 (179616) survived and regained normal body weight through amelioration of disease at discrete phases, indicating that TREX1 substrates are ligands of the ISD pathway. Single-stranded DNA derived from endogenous retroelements accumulated in Trex1 -/- cells, and Trex1 metabolized reverse-transcribed DNA. Stetson et al. (2008) concluded that TREX1 is an essential negative regulator of the ISD response and represents a mechanism to prevent autoimmunity caused by endogenous retroelements. </p><p>Yan et al. (2010) observed enhanced Ifnb (147640) and Il6 (147620) expression in Trex1 -/- mouse embryonic fibroblasts (MEFs) infected with pseudotyped human immunodeficiency virus (HIV)-1 (see 609423) compared with uninfected Trex1 -/- MEFs or infected wildtype MEFs. Ifnb induction was mediated by reverse transcribed HIV in an Irf3 (603734)-dependent manner. HIV reverse transcripts accumulated in Trex -/- MEFs. HIV-stimulated Ifnb from Trex1 -/- MEFs inhibited HIV. Yan et al. (2010) observed an increase in cytosolic HIV DNA and reduced viral spreading, accompanied by increased IFNA (147660) and IFNB expression, in human monocyte-derived macrophages treated with small interfering RNA (siRNA) against TREX1 and subsequently infected with HIV-1. Treatment of Trex1 -/- MEFs with siRNA against genes related to innate immunity showed that HIV DNA was detected by a pathway that signaled through Sting (TMEM173; 612374), Tbk1 (604834), and Irf3 but not nucleic acid sensors. Yan et al. (2010) proposed that HIV-1 uses TREX1 to avoid triggering antiviral innate immunity. </p><p>Using mutation analysis with recombinant human TREX1, Fye et al. (2011) found that arg174 and lys175 within the flexible loop and arg128 in the catalytic core contributed to single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) degradation. TREX1 degraded endonuclease-treated hamster liver nuclei, suggesting that TREX1 contributes to apoptosis-associated DNA degradation. </p><p>Mutations in the TREX1 gene cause the type I IFN-associated autoimmune disease Aicardi-Goutieres syndrome (AGS1; 225750). Ablasser et al. (2014) found that knockout of the DNA sensor Cgas (MB21D1; 613973) in Trex1-deficient mouse cells abrogated spontaneous induction of IFN-stimulated genes. They concluded that CGAS is a nonredundant sensor for endogenous DNA species and proposed that it may have value for the development of novel therapeutic approaches in sterile inflammatory conditions. </p><p>By differentiating neural stem cells into astrocytes and treating them with short hairpin RNA (shRNAs) to AGS genes, Cuadrado et al. (2015) observed increased apoptosis in cells treated with shRNA to TREX1. Similarly, TREX1 silencing led to reduced proliferation of endothelial cells, but not of cells involved in angiogenesis. Silencing of TREX1 or SAMHD1 (606754), but not RNASEH2A (606034) or ADAR1 (146920), resulted in enhanced expression of IFN-stimulated genes (ISGs), such as IFIT1 (147690). TREX1 shRNA treatment led to increased production of proinflammatory and chemotactic cytokines. Cuadrado et al. (2015) proposed that activation of antiviral status in astrocytes and endothelial cells may lead to cerebral pathology and ultimately severe disease in AGS. </p><p>Maciejowski et al. (2020) examined the mechanism underlying chromothripsis and kataegis using an in vitro telomere crisis model in human cells and showed that the cytoplasmic exonuclease TREX1, which promotes resolution of dicentric chromosomes, played a prominent role in chromothriptic fragmentation. In the absence of TREX1, genome alterations induced by telomere crisis primarily involved breakage-fusion-bridge cycles and simple genome rearrangements rather than chromothripsis. Kataegis observed at chromothriptic breakpoints was due to cytosine deamination by APOBEC3B (607110). Maciejowski et al. (2020) concluded that chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B. </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>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">
|
|
<p><strong><em>Aicardi-Goutieres Syndrome 1</em></strong></p><p>
|
|
In affected members of 10 families with Aicardi-Goutieres syndrome (AGS1; 225750), Crow et al. (2006) identified 5 different mutations in the TREX1 gene in homozygous or compound heterozygous state (see, e.g., 606609.0001-606609.0004). One of the mutations, R114H (606609.0001), was identified in 7 European pedigrees. Crow et al. (2006) identified a homozygous mutation in the TREX1 gene (606609.0002) in a patient originally diagnosed with Cree encephalitis, indicating that Cree encephalitis is the same disorder as AGS1. </p><p>Rice et al. (2007) described a de novo heterozygous TREX1 mutation, affecting a critical catalytic residue in TREX1 (D200N; 606609.0006), that resulted in typical Aicardi-Goutieres syndrome, thus defining a dominant form of the disorder. </p><p>Haaxma et al. (2010) reported a second patient with Aicardi-Goutieres syndrome and a de novo heterozygous TREX1 mutation (D18N; 606609.0007). The D18N mutation had previously been identified in heterozygosity by Lee-Kirsch et al. (2007) in a family with chilblain lupus. </p><p><strong><em>Susceptibility to Systemic Lupus Erythematosus</em></strong></p><p>
|
|
Aicardi-Goutieres syndrome shows overlap with systemic erythematosus (SLE; 152700) at both clinical and pathologic levels. Lee-Kirsch et al. (2007) analyzed the TREX1 gene in 417 patients with SLE and 1,712 controls and identified heterozygosity for a 3-prime UTR variant and 11 nonsynonymous changes in 12 patients (see, e.g., 606609.0001). They found only 2 nonsynonymous changes in 2 controls (p = 1.7 X 10(-7), relative risk = 25.3). In vitro studies of 2 frameshift mutations revealed that both caused altered subcellular distribution. </p><p><strong><em>Chilblain Lupus</em></strong></p><p>
|
|
Rice et al. (2007) reported a heterozygous TREX1 mutation (606609.0005) causing familial chilblain lupus (CHBL; 610448), a rare cutaneous form of SLE. </p><p>In affected members of the large 5-generation German family with chilblain lupus in which the disease was mapped to chromosome 3p21-p14 by Lee-Kirsch et al. (2006), Lee-Kirsch et al. (2007) identified heterozygosity for a missense mutation (D18N; 606609.0007) in the TREX1 gene. </p><p><strong><em>Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations</em></strong></p><p>
|
|
In 9 families with autosomal dominant retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS; 192315), Richards et al. (2007) identified 5 different heterozygous frameshift mutations at the C terminus of the TREX1 gene (see, e.g., 606609.0008 and 606609.0009). In expression studies, the truncated proteins retained exonuclease activity but lost normal perinuclear localization. </p>
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>Genotype/Phenotype Correlations</strong>
|
|
</span>
|
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</h4>
|
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</div>
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|
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<span class="mim-text-font">
|
|
<p>The TREX1 D200N and D18N dominant heterozygous mutations are associated with AGS1 and CHBL, respectively. Using exonuclease enzyme analysis, Lehtinen et al. (2008) showed that TREX1 heterodimers containing wildtype TREX1 and either D200N or D18N mutant proteins were completely deficient in degrading dsDNA and degraded ssDNA at an approximately 2-fold lower rate than wildtype TREX1. In addition, D200N- and D18N-containing homo- and heterodimers inhibited the dsDNA degradation activity of wildtype TREX1, providing an explanation for the dominant phenotype of the mutant alleles. In contrast, the R114H mutation, which causes AGS1 when present as a homozygous mutation and SLE when present as a heterozygous mutation, had dysfunctional dsDNA and ssDNA degradation activities as a homodimer, but it was functional as a heterodimer. The R114H homodimer lacked inhibitory activity against wildtype TREX1, supporting the recessive genetics of the R114H mutation in AGS1. Lehtinen et al. (2008) concluded that the dysfunctional dsDNA activities of the disease-related TREX1 mutants could account for persistent dsDNA from dying cells leading to an aberrant autoimmune response in these disorders. </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>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">
|
|
<p>Morita et al. (2004) found that Trex1 -/- mice developed inflammatory myocarditis, suggesting a role for this enzyme in immune regulation. </p><p>Peschke et al. (2016) found that mice with conditional loss of Trex1 in dendritic cells had increased Ifn-inducible gene expression (e.g., IFI44; 610468) and autoimmunity, as assessed by histologic analysis. Loss of Trex1 in keratinocytes or microglia resulted in Ifn production but did not induce inflammation. Inactivation of Trex1 in B cells, cardiomyocytes, neurons, or astrocytes did not produce detectable responses. Peschke et al. (2016) concluded that TREX1 expression in dendritic cells is essential to prevent loss of self-tolerance resulting from aberrant detection of endogenous DNA. </p><p>Simpson et al. (2020) found that mice expressing the catalytically inactive D18N Trex1 mutation developed lupus-like autoimmunity associated with self-DNA sensing and abnormal expression of IFN-alpha and -beta in T cells. Trex1 inactivation resulted in activated T cells that constitutively expressed all molecular components of the DNA sensing and signaling pathways required for cytosolic DNA detection and IFN-alpha/beta production, leading to abnormal production of type I IFN in T cells and, consequently, autoimmunity. </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">
|
|
<strong>ALLELIC VARIANTS</strong>
|
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</span>
|
|
<strong>11 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">
|
|
<strong>.0001 AICARDI-GOUTIERES SYNDROME 1</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">
|
|
SYSTEMIC LUPUS ERYTHEMATOSUS, SUSCEPTIBILITY TO, INCLUDED
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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TREX1, ARG114HIS
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<br />
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SNP: rs72556554,
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|
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gnomAD: rs72556554,
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|
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ClinVar: RCV000004396, RCV000004397, RCV000256102, RCV000850611, RCV001266495, RCV002281693, RCV004540989, RCV005025005
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p />
|
|
<p><strong><em>Aicardi-Goutieres Syndrome 1</em></strong></p><p>
|
|
In affected members of 7 families of European origin with Aicardi-Goutieres syndrome-1 (AGS1; 225750), Crow et al. (2006) identified a 341G-A transition in the TREX1 gene, resulting in an arg114-to-his (R114H) substitution at a residue predicted to be involved in protein dimerization. Five of the families were homozygous for the mutation and 2 were compound heterozygous with another TREX1 mutation (606609.0003). Patient-derived fibroblasts showed no detectable TREX1 3-prime exonuclease activity. </p><p>In an extensive study of the clinical and molecular phenotypes of Aicardi-Goutieres syndrome, Rice et al. (2007) found biallelic mutations in TREX1 in 31 of 127 families with the clinical diagnosis of the disorder. Eighteen families, 14 of which were of northern European origin, were homozygous (15) or compound heterozygous (3) for the 341G-A transition (R114H). Notably, all R114H homozygotes were also homozygous for the T allele of a SNP at position 531. This allele exhibited highly significant (P less than 0.001) overrepresentation in patients compared with controls (with a T allele population frequency of 0.4), suggesting that R114H might be an ancient founder mutation. </p><p><strong><em>Systemic Lupus Erythematosus, Susceptibility to</em></strong></p><p>
|
|
Lee-Kirsch et al. (2007) analyzed the TREX1 gene in 417 patients with systemic lupus erythematosus (152700) and identified heterozygosity for the R114H mutation in a European female patient who had nephritis, arthritis, and antinuclear and anti-dsDNA antibodies. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0002 AICARDI-GOUTIERES SYNDROME 1</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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TREX1, ARG164TER
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<br />
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SNP: rs78218009,
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ClinVar: RCV000004398, RCV000378411, RCV001384591, RCV004532286
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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 patient with Cree encephalitis, also known as Aicardi-Goutieres syndrome-1 (AGS1; 225750), who was born of consanguineous parents, Crow et al. (2006) identified a homozygous 490C-T transition in the TREX1 gene, resulting in an arg164-to-ter (R164X) substitution. A lymphoblastoid cell line derived from the patient showed no detectable 3-prime exonuclease activity. The findings confirmed that Cree encephalitis and AGS1 are the same disorder. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0003 AICARDI-GOUTIERES SYNDROME 1</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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TREX1, 3-BP INS, 600GAT
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<br />
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SNP: rs74556809,
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ClinVar: RCV000004399, RCV001063407, RCV001794431, RCV005025006
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In affected members of 2 unrelated families with Aicardi-Goutieres syndrome (AGS1; 225750), Crow et al. (2006) identified compound heterozygosity for 2 mutations in the TREX1 gene: a 3-bp insertion (600_601insGAT), resulting in duplication of an aspartate residue involved in divalent cation binding within the catalytic site, and R114H (606609.0001). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0004 AICARDI-GOUTIERES SYNDROME 1</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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TREX1, VAL201ASP
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<br />
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SNP: rs78408272,
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ClinVar: RCV000004400, RCV001093076
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with Aicardi-Goutieres syndrome (AGS1; 225750), who was born of consanguineous Turkish parents, Crow et al. (2006) identified a homozygous 602T-A transversion in the TREX1 gene, resulting in a val201-to-asp (V201D) substitution in the catalytic site of the protein. Patient-derived fibroblasts showed no detectable TREX1 3-prime exonuclease activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 CHILBLAIN LUPUS</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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TREX1, 1-BP DUP, 375T
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<br />
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SNP: rs1575292873,
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ClinVar: RCV001804149, RCV004719620, RCV005031387
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a nonconsanguineous Bangladeshi family, Rice et al. (2007) found association between chilblain lupus (CHBL1; 610448) and a heterozygous mutation in the TREX1 gene, the duplication of a single base (375dupT) that resulted in a truncated protein missing the last 188 amino acids. The mutation was present in 3 affected sibs; it was found also in a fourth sib with a subclinical phenotype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 AICARDI-GOUTIERES SYNDROME 1, AUTOSOMAL DOMINANT</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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TREX1, ASP200ASN
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<br />
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SNP: rs78846775,
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ClinVar: RCV000004402, RCV000114331, RCV002512754
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a child with a classic history of Aicardi-Goutieres syndrome (AGS1; 225750), who was born to nonconsanguineous Scottish parents, Rice et al. (2007) found heterozygosity for a missense mutation in the TREX1 gene: a 598G-A transition that resulted in a substitution of asparagine for aspartic acid at codon 200 (D200N). Both parents had a homozygous wildtype genotype at this position, suggesting a de novo occurrence. Differentiation of the maternal and paternal alleles was possible because of a frequently observed C-to-T SNP at position 531, which allowed the authors to demonstrate that the mutation has arisen on the maternal allele. A standard exonuclease assay indicated close-to-normal TREX1 enzymatic activity. Rice et al. (2007) hypothesized that the aspartic acid at position 200 of TREX1 represents one of 4 residues essential for coordinating 2 magnesium ions involved in DNA binding and catalysis, and that the D200N mutation represents a gain-of-function mutation conferring altered substrate specificity, DNA binding, or protein-protein interaction which would not be detected in a standard TREX1 exonuclease assay. </p><p>Fye et al. (2011) stated that asp18 and asp200 are the 2 aspartates that coordinate the divalent metal ion Mg(2+) at the TREX1 active site and contribute to DNA binding and catalysis. They found that homodimers of recombinant human TREX1 containing D200N or D18N (606609.0007) mutations had negligible nuclease activity against ssDNA and dsDNA compared with wildtype. Heterodimers of wildtype TREX1 with D18N or D200N TREX1 mutants had more modestly reduced ssDNA nuclease activity, but profoundly reduced dsDNA nuclease activity, compared with wildtype homodimers. Fye et al. (2011) concluded that the dominant phenotypes of asp18 and asp200 mutations relate predominantly to impaired dsDNA degradation and indicate that TREX1 dsDNA degradation activity is fundamental to the prevention of autoimmunity. </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>.0007 CHILBLAIN LUPUS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
AICARDI-GOUTIERES SYNDROME 1, AUTOSOMAL DOMINANT, INCLUDED
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
TREX1, ASP18ASN
|
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|
|
|
<br />
|
|
|
|
SNP: rs121908117,
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|
|
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|
|
|
ClinVar: RCV000004405, RCV000114329, RCV000323773, RCV000819829, RCV001804150
|
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|
|
</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Chilblain Lupus</em></strong></p><p>
|
|
In affected members of the large 5-generation German family with chilblain lupus (CHBL1; 610448) described by Lee-Kirsch et al. (2006), Lee-Kirsch et al. (2007) identified heterozygosity for a 52G-A transition in exon 1 of the TREX1 gene, resulting in an asp18-to-asn (D18N) substitution at a highly conserved residue critical for catalytic activity. The mutation was not found in unaffected family members or in 400 control chromosomes. Recombinant mutant TREX1 homodimers were enzymatically inactive, whereas mutant/wildtype heterodimers had approximately 40% of the activity of wildtype dimers, indicating that D18N is a loss-of-function allele that does not exhibit a dominant-negative effect. Compared to control cells, patient-derived lymphoblastoid cells were substantially less sensitive to cell death after treatment with granzyme A (GZMA; 140050) but not granzyme B (GZMB; 123910), indicating that D18N specifically interferes with GZMA-mediated cell death in the caspase-independent form of apoptosis. </p><p><strong><em>Aicardi-Goutieres Syndrome 1</em></strong></p><p>
|
|
In a 16-year-old girl with relatively mild Aicardi-Goutieres syndrome (AGS1; 225750), who was negative for mutation in other known AGS genes, Haaxma et al. (2010) identified a de novo heterozygous D18N missense mutation in the TREX1 gene. The mutation was not found in either parent or in 200 control chromosomes. The patient also displayed features of mitochondrial disease, with cytochrome oxidase-negative and ragged-red fibers seen on histologic examination of the quadriceps muscle; biochemical measurements showed decreased overall energy production (ATP and CrP) in the presence of normal activities of individual respiratory chain complexes, again compatible with mitochondrial dysfunction. However, heteroduplex analysis of the entire mitochondrial DNA did not show any mutations. This patient also had peripheral neuropathy with prominent axonal loss and disturbances of myelination without strict demyelination. </p><p>Fye et al. (2011) stated that asp18 and asp200 are the 2 aspartates that coordinate the divalent metal ion Mg(2+) at the TREX1 active site and contribute to DNA binding and catalysis. They found that homodimers of recombinant human TREX1 containing D200N (606609.0006) or D18N mutations had negligible nuclease activity against ssDNA and dsDNA compared with wildtype. Heterodimers of wildtype TREX1 with D18N or D200N TREX1 mutants had more modestly reduced ssDNA nuclease activity, but profoundly reduced dsDNA nuclease activity, compared with wildtype homodimers. Fye et al. (2011) concluded that the dominant phenotypes of asp18 and asp200 mutations relates predominantly to impaired dsDNA degradation and indicates that TREX1 dsDNA degradation activity is fundamental to the prevention of autoimmunity. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 VASCULOPATHY, RETINAL, WITH CEREBRAL LEUKOENCEPHALOPATHY AND SYSTEMIC MANIFESTATIONS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TREX1, 1-BP INS, 3688G
|
|
|
|
|
|
<br />
|
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|
|
SNP: rs1553820434,
|
|
|
|
|
|
|
|
ClinVar: RCV000004403, RCV000519088, RCV000795266
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 families with autosomal dominant retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS; 192315), including 2 North American families previously reported by Grand et al. (1988) and 1 Dutch pedigree originally described by Storimans et al. (1991), Richards et al. (2007) identified heterozygosity for a 1-bp insertion (3688G) at the C terminus of the TREX1 gene, resulting in a frameshift at val235 (V235fs). Haplotype analysis suggested that these families were not related. The mutation was not found in 192 Caucasian, 192 Chinese, or 300 Dutch control alleles. In expression studies, the truncated protein retained exonuclease activity but lost normal perinuclear localization. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 VASCULOPATHY, RETINAL, WITH CEREBRAL LEUKOENCEPHALOPATHY AND SYSTEMIC MANIFESTATIONS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TREX1, 4-BP DUP, 3727GTCA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1560113283,
|
|
|
|
|
|
|
|
ClinVar: RCV000004406
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a North American family of Chinese ancestry with autosomal dominant retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS; 192315), previously reported by Jen et al. (1997), Richards et al. (2007) identified heterozygosity for a 4-bp duplication (3727dupGTCA) at the C terminus of the TREX1 gene, resulting in a frameshift at thr249 (T249fs). The mutation was not found in 192 Caucasian, 192 Chinese, or 300 Dutch control alleles. In expression studies, the truncated protein retained exonuclease activity but lost normal perinuclear localization. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 AICARDI-GOUTIERES SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TREX1, ARG169HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs72556554,
|
|
|
|
|
|
gnomAD: rs72556554,
|
|
|
|
|
|
ClinVar: RCV000004396, RCV000004397, RCV000256102, RCV000850611, RCV001266495, RCV002281693, RCV004540989, RCV005025005
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 2-month-old boy (patient 4) with Aicardi-Goutieres syndrome (AGS1; 225750), Adang et al. (2018) identified compound heterozygous mutations in the TREX1 gene: a c.506G-A transition, resulting in an arg169-to-his (R169H) substitution, and a 1-bp deletion (c.581delC), resulting in frameshift (Arg194fs). The patient presented with pulmonary hypertension that ultimately caused his death at 12 weeks of age. He also had CNS perivascular calcifications and gastrointestinal symptoms, but no dermatologic manifestations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 AICARDI-GOUTIERES SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TREX1, 1-BP DEL, 581C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1575293518,
|
|
|
|
|
|
|
|
ClinVar: RCV000754080
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 1-bp deletion (c.581delC) in the TREX1 gene that was found in compound heterozygous state in a patient with Aicardi-Goutieres syndrome (AGS1; 225750) by Adang et al. (2018), see 606609.0010. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
</div>
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|
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</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">
|
|
Ablasser, A., Hemmerling, I., Schmid-Burgk, J. L., Behrendt, R., Roers, A., Hornung, V.
|
|
<strong>TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner.</strong>
|
|
J. Immun. 192: 5993-5997, 2014.
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|
|
[PubMed: 24813208]
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[Full Text: https://doi.org/10.4049/jimmunol.1400737]
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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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Adang, L. A., Frank, D. B., Gilani, A., Takanohashi, A., Ulrick, N., Collins, A., Cross, Z., Galambos, C., Helman, G., Kanaan, U., Keller, S., Simon, D., Sherbini, O., Hanna, B. D., Vanderver, A. L.
|
|
<strong>Aicardi Goutieres syndrome is associated with pulmonary hypertension.</strong>
|
|
Molec. Genet. Metab. 125: 351-358, 2018.
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[PubMed: 30219631]
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[Full Text: https://doi.org/10.1016/j.ymgme.2018.09.004]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Chowdhury, D., Beresford, P. J., Zhu, P., Zhang, D., Sung, J.-S., Demple, B., Perrino, F. W., Lieberman, J.
|
|
<strong>The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death.</strong>
|
|
Molec. Cell 23: 133-142, 2006.
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|
[PubMed: 16818237]
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[Full Text: https://doi.org/10.1016/j.molcel.2006.06.005]
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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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Crow, Y. J., Hayward, B. E., Parmar, R., Robins, P., Leitch, A., Ali, M., Black, D. N., van Bokhoven, H., Brunner, H. G., Hamel, B. C., Corry, P. C., Cowan, F. M., and 14 others.
|
|
<strong>Mutations in the gene encoding the 3-prime-5-prime DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus.</strong>
|
|
Nature Genet. 38: 917-920, 2006.
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[PubMed: 16845398]
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[Full Text: https://doi.org/10.1038/ng1845]
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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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Cuadrado, E., Michailidou, I., van Bodegraven, E. J., Jansen, M. H., Sluijs, J. A., Geerts, D., Couraud, P.-O., De Filippis, L., Vescovi, A. L., Kuijpers, T. W., Hol, E. M.
|
|
<strong>Phenotypic variation in Aicardi-Goutieres syndrome explained by cell-specific IFN-stimulated gene response and cytokine release.</strong>
|
|
J. Immun. 194: 3623-3633, 2015.
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|
[PubMed: 25769924]
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[Full Text: https://doi.org/10.4049/jimmunol.1401334]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Fye, J. M., Orebaugh, C. D., Coffin, S. R., Hollis, T., Perrino, F. W.
|
|
<strong>Dominant mutations of the TREX1 exonuclease gene in lupus and Aicardi-Goutieres syndrome.</strong>
|
|
J. Biol. Chem. 286: 32373-32382, 2011.
|
|
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|
|
|
[PubMed: 21808053]
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[Full Text: https://doi.org/10.1074/jbc.M111.276287]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Grand, M. G., Kaine, J., Fulling, K., Atkinson, J., Dowton, S. B., Farber, M., Craver, J., Rice, K.
|
|
<strong>Cerebroretinal vasculopathy.</strong>
|
|
Ophthalmology 95: 649-659, 1988.
|
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|
|
[PubMed: 3174024]
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[Full Text: https://doi.org/10.1016/s0161-6420(88)33131-3]
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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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Haaxma, C. A., Crow, Y. J., van Steensel, M. A. M., Lammens, M. M. Y., Rice, G. I., Verbeek, M. M., Willemsen, M. A. A. P.
|
|
<strong>A de novo p.Asp18Asn mutation in TREX1 in a patient with Aicardi-Goutieres syndrome.</strong>
|
|
Am. J. Med. Genet. 152A: 2612-2617, 2010.
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|
[PubMed: 20799324]
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[Full Text: https://doi.org/10.1002/ajmg.a.33620]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Hoss, M., Robins, P., Naven, T. J. P., Pappin, D. J. C., Sgouros, J., Lindahl, T.
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|
<strong>A human DNA editing enzyme homologous to the Escherichia coli DnaQ/MutD protein.</strong>
|
|
EMBO J. 18: 3868-3875, 1999.
|
|
|
|
|
|
[PubMed: 10393201]
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[Full Text: https://doi.org/10.1093/emboj/18.13.3868]
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</p>
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</li>
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