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- *191163 - TUMOR NECROSIS FACTOR-ALPHA-INDUCED PROTEIN 3; TNFAIP3
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- OMIM
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<p>
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<span class="h4">*191163</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<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/191163">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<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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</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=ENSG00000118503;t=ENST00000612899" 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=7128" 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=191163" 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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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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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=ENSG00000118503;t=ENST00000612899" 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_001270507,NM_001270508,NM_006290,XM_005267119,XM_011536095,XM_011536096,XM_024446532,XM_024446533,XM_047419282,XM_047419283,XM_047419284,XM_047419285" 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_001270508" 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=191163" 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="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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<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=01857&isoform_id=01857_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/TNFAIP3" 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/112894,177866,5454132,7018446,28932978,56112360,88683077,89365979,119568308,119568309,119568310,119568311,189053548,225348432,225348436,225348438,225348440,225348442,225348444,225348446,225348448,225348450,225348452,225348454,225348456,225348459,225348461,225348463,337294550,395393995,395393997,530384006,767943502,767943504,1370508562,1370508564,2217362898,2217362902,2217362906,2217362908,2462610297,2462610299,2462610301,2462610303,2462610305,2462610307,2462610309" 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/P21580" 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 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=7128" 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=ENSG00000118503;t=ENST00000612899" 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=TNFAIP3" 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=TNFAIP3" 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+7128" 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/TNFAIP3" 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:7128" 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/7128" 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=chr6&hgg_gene=ENST00000612899.5&hgg_start=137866349&hgg_end=137883312&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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<div 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=191163[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 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=191163[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/TNFAIP3/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/ENSG00000118503" 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=TNFAIP3" 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=TNFAIP3" 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=TNFAIP3" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=TNFAIP3&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/PA36593" 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:11896" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1196377" 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/TNFAIP3#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:1196377" 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/7128/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=7128" 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://zfin.org/ZDB-GENE-100212-2" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7128" 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=TNFAIP3&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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191163
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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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TUMOR NECROSIS FACTOR-ALPHA-INDUCED PROTEIN 3; TNFAIP3
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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A20<br />
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OTU DOMAIN-CONTAINING PROTEIN 7C; OTUD7C
|
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</span>
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TNFAIP3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TNFAIP3</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/6/896?start=-3&limit=10&highlight=896">6q23.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr6:137866349-137883312&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'})">6:137,866,349-137,883,312</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/6/896?start=-3&limit=10&highlight=896">
|
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6q23.3
|
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</a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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Autoinflammatory syndrome, familial, Behcet-like 1
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</span>
|
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/616744"> 616744 </a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/191163" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/191163" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
|
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|
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
|
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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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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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>The TNFAIP3 gene encodes an ubiquitin-editing enzyme with a critical function in the inhibition of key proinflammatory molecules to negatively regulate inflammation and the immune response (summary by <a href="#1" class="mim-tip-reference" title="Aeschlimann, F. A., Batu, E. D., Canna, S. W., Go, E., Gul, A., Hoffmann, P., Leavis, H. L., Ozen, S., Schwartz, D. M., Stone, D. L., van Royen-Kerkof, A., Kastner, D. L., Aksentijevich, I., Laxer, R. M. <strong>A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease.</strong> Ann. Rheum. Dis. 77: 728-735, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29317407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29317407</a>] [<a href="https://doi.org/10.1136/annrheumdis-2017-212403" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29317407">Aeschlimann et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29317407" 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>A20 is a cytoplasmic zinc finger protein that inhibits nuclear factor kappa-B (NFKB; see <a href="/entry/164011">164011</a>) activity and tumor necrosis factor (TNF; <a href="/entry/191160">191160</a>)-mediated programmed cell death. TNF dramatically increases A20 mRNA expression in all tissues (<a href="#7" class="mim-tip-reference" title="Dixit, V. M., Green, S., Sarma, V., Holzman, L. B., Wolf, F. W., O'Rourke, K., Ward, P. A., Prochownik, E. V., Marks, R. M. <strong>Tumor necrosis factor-alpha induction of novel gene products in human endothelial cells including a macrophage-specific chemotaxin.</strong> J. Biol. Chem. 265: 2973-2978, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2406243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2406243</a>]" pmid="2406243">Dixit et al., 1990</a>; <a href="#14" class="mim-tip-reference" title="Lee, E. G., Boone, D. L., Chai, S., Libby, S. L., Chien, M., Lodolce, J. P., Ma, A. <strong>Failure to regulate TNF-induced NF-kappa-B and cell death responses in A20-deficient mice.</strong> Science 289: 2350-2354, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11009421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11009421</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11009421[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.289.5488.2350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11009421">Lee et al., 2000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11009421+2406243" 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>Cytokines such as TNF profoundly affect endothelial cell function, promoting, for example, interaction with leukocytes and inducing a procoagulant phenotype. Changes of this nature are likely to be central to the proinflammatory effects of TNF. <a href="#7" class="mim-tip-reference" title="Dixit, V. M., Green, S., Sarma, V., Holzman, L. B., Wolf, F. W., O'Rourke, K., Ward, P. A., Prochownik, E. V., Marks, R. M. <strong>Tumor necrosis factor-alpha induction of novel gene products in human endothelial cells including a macrophage-specific chemotaxin.</strong> J. Biol. Chem. 265: 2973-2978, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2406243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2406243</a>]" pmid="2406243">Dixit et al. (1990)</a> analyzed TNF-induced primary response genes in human umbilical vein endothelial cells. Of the 6 induced cDNAs identified, 2 encoded paracrine factors, neutrophil chemotactic factor (<a href="/entry/146930">146930</a>) and monocyte chemotactic factor (<a href="/entry/158105">158105</a>); 1 encoded a membrane receptor for neutrophils, endothelial leukocyte adhesion molecule 1 (ELAM1; <a href="/entry/131210">131210</a>); and 3 encoded hitherto undescribed TNF primary response genes. On exposure of endothelial cells to TNF, there was a rapid and substantial increase in the levels of mRNA encoding the 6 genes, which were further superinduced by cycloheximide. Thus these represent primary response genes, as their induction does not depend on protein synthesis. One of the 3 new proteins, designated A20, was found on sequence analysis to code for a novel zinc finger protein (<a href="#20" class="mim-tip-reference" title="Opipari, A. W., Jr., Boguski, M. S., Dixit, V. M. <strong>The A20 cDNA induced by tumor necrosis factor-alpha encodes a novel type of zinc finger protein.</strong> J. Biol. Chem. 265: 14705-14708, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2118515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2118515</a>]" pmid="2118515">Opipari et al., 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2118515+2406243" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#11" class="mim-tip-reference" title="Hartz, P. A. <strong>Personal Communication.</strong> Baltimore, Md. 12/15/2014."None>Hartz (2014)</a> mapped the TNFAIP3 gene to chromosome 6q23.3 based on an alignment of the TNFAIP3 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AL157444" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AL157444</a>) with the genomic sequence (GRCh38).</p><p><a href="#28" class="mim-tip-reference" title="Wolfrum, S., Teupser, D., Tan, M., Chen, K. Y., Breslow, J. L. <strong>The protective effect of A20 on atherosclerosis in apolipoprotein E-deficient mice is associated with reduced expression of NF-kappa-B target genes.</strong> Proc. Nat. Acad. Sci. 104: 18601-18606, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18006655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18006655</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18006655[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0709011104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18006655">Wolfrum et al. (2007)</a> stated that the mouse Tnfaip3 gene maps to proximal chromosome 10. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18006655" 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="#19" class="mim-tip-reference" title="O'Reilly, S. M., Moynagh, P. N. <strong>Regulation of Toll-like receptor 4 signalling by A20 zinc finger protein.</strong> Biochem. Biophys. Res. Commun. 303: 586-593, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12659860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12659860</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)00389-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12659860">O'Reilly and Moynagh (2003)</a> expressed A20 and TLR4 (<a href="/entry/603030">603030</a>) in a human embryonic kidney cell line and observed inhibition of NFKB activation after LPS stimulation. Mutation analysis showed that the C-terminal zinc finger domain of A20 was sufficient for NFKB inhibition, whereas the full-length protein was required for inhibition of AP1 (<a href="/entry/165160">165160</a>) activation and for induction of IL8 (<a href="/entry/146930">146930</a>). <a href="#19" class="mim-tip-reference" title="O'Reilly, S. M., Moynagh, P. N. <strong>Regulation of Toll-like receptor 4 signalling by A20 zinc finger protein.</strong> Biochem. Biophys. Res. Commun. 303: 586-593, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12659860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12659860</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)00389-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12659860">O'Reilly and Moynagh (2003)</a> concluded that A20 modulates TLR4 signaling at or downstream of MEKK1 (MAP3K1; <a href="/entry/600982">600982</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12659860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Wertz, I. E., O'Rourke, K. M., Zhou, H., Eby, M., Aravind, L., Seshagiri, S., Wu, P., Wiesmann, C., Baker, R., Boone, D. L., Ma, A., Koonin, E. V., Dixit, V. M. <strong>De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappa-B signalling.</strong> Nature 430: 694-699, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15258597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15258597</a>] [<a href="https://doi.org/10.1038/nature02794" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15258597">Wertz et al. (2004)</a> demonstrated that A20 downregulates NF-kappa-B signaling through the cooperative activity of its 2 ubiquitin-editing domains. The N-terminal domain of A20, which is a deubiquitinating enzyme of the OTU (ovarian tumor) family, removes lysine-63-linked ubiquitin chains from receptor-interacting protein (RIP; <a href="/entry/603453">603453</a>), an essential mediator of the proximal TNF receptor-1 (TNFR1; <a href="/entry/191190">191190</a>) signaling complex. The C-terminal domain of A20, composed of 7 C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with lysine-48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation. <a href="#27" class="mim-tip-reference" title="Wertz, I. E., O'Rourke, K. M., Zhou, H., Eby, M., Aravind, L., Seshagiri, S., Wu, P., Wiesmann, C., Baker, R., Boone, D. L., Ma, A., Koonin, E. V., Dixit, V. M. <strong>De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappa-B signalling.</strong> Nature 430: 694-699, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15258597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15258597</a>] [<a href="https://doi.org/10.1038/nature02794" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15258597">Wertz et al. (2004)</a> defined a novel ubiquitin ligase domain and identified 2 sequential mechanisms by which A20 downregulates NF-kappa-B signaling. They also provided an example of a protein containing separate ubiquitin ligase and deubiquitinating domains, both of which participate in mediating a distinct regulatory effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15258597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Vendrell, J. A., Ghayad, S., Ben-Larbi, S., Dumontet, C., Mechti, N., Cohen, P. A. <strong>A20/TNFAIP3, a new estrogen-regulated gene that confers tamoxifen resistance in breast cancer cells.</strong> Oncogene 26: 4656-4667, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17297453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17297453</a>] [<a href="https://doi.org/10.1038/sj.onc.1210269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17297453">Vendrell et al. (2007)</a> found that expression of A20 was downregulated by estradiol treatment of an estrogen receptor (ER; see <a href="/entry/133430">133430</a>)-positive, hormone-responsive human breast cancer cell line. Conversely, A20 was highly expressed in ER-negative cell lines. Overexpression of A20 in MCF7 breast cancer cells conferred resistance to tamoxifen-induced cytotoxicity that was associated with dysregulation of BAX (<a href="/entry/600040">600040</a>), BCL2 (<a href="/entry/151430">151430</a>), BAK (<a href="/entry/600516">600516</a>), phospho-BAD (<a href="/entry/603167">603167</a>), and several cyclins (e.g., CCNA2; <a href="/entry/123835">123835</a>). A20 was overexpressed in tamoxifen-resistant cell lines, and high A20 expression was also observed in more aggressive breast tumors. <a href="#25" class="mim-tip-reference" title="Vendrell, J. A., Ghayad, S., Ben-Larbi, S., Dumontet, C., Mechti, N., Cohen, P. A. <strong>A20/TNFAIP3, a new estrogen-regulated gene that confers tamoxifen resistance in breast cancer cells.</strong> Oncogene 26: 4656-4667, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17297453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17297453</a>] [<a href="https://doi.org/10.1038/sj.onc.1210269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17297453">Vendrell et al. (2007)</a> concluded that A20 is a key protein involved in tamoxifen resistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17297453" 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="Song, X.-T., Evel-Kabler, K., Shen, L., Rollins, L., Huang, X. F., Chen, S.-Y. <strong>A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression.</strong> Nature Med. 14: 258-265, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18311150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18311150</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18311150[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/nm1721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18311150">Song et al. (2008)</a> found that silencing of A20 allowed mouse dendritic cells (DCs) to hyperactivate cytotoxic lymphocytes and T-helper cells and inhibit regulatory T cells (Tregs), enhancing infiltration of tumor-infiltrating lymphocytes into tumors. They proposed that the inhibitory effects of A20-silenced DCs on Tregs may tip the balance from immune suppression to antitumor immunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18311150" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Shembade, N., Ma, A., Harhaj, E. W. <strong>Inhibition of NF-kappa-B signaling by A20 through disruption of ubiquitin enzyme complexes.</strong> Science 327: 1135-1139, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20185725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20185725</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20185725[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1182364" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20185725">Shembade et al. (2010)</a> showed that A20 inhibits the E3 ligase activities of TRAF6 (<a href="/entry/602355">602355</a>), TRAF2 (<a href="/entry/601895">601895</a>), and cIAP1 (<a href="/entry/601712">601712</a>) by antagonizing interactions with E2 ubiquitin-conjugating enzymes UBC13 (<a href="/entry/603679">603679</a>) and UBCH5C (<a href="/entry/602963">602963</a>). A20, together with the regulatory molecule TAX1BP1 (<a href="/entry/605326">605326</a>), interacted with UBC13 and UBCH5C and triggered their ubiquitination and proteasome-dependent degradation. These findings suggested a mechanism of A20 action in the inhibition of inflammatory signaling pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20185725" 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 immunoblot analysis, <a href="#6" class="mim-tip-reference" title="Coornaert, B., Baens, M., Heyninck, K., Bekaert, T., Haegman, M., Staal, J., Sun, L., Chen, Z. J., Marynen, P., Beyaert, R. <strong>T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappa-B inhibitor A20.</strong> Nature Immun. 9: 263-271, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18223652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18223652</a>] [<a href="https://doi.org/10.1038/ni1561" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18223652">Coornaert et al. (2008)</a> showed that MALT1 (<a href="/entry/604860">604860</a>) is a functional cysteine protease activated by T cell receptor stimulation and that it rapidly cleaves A20 after arg439, impairing its NFKB (see <a href="/entry/164011">164011</a>) inhibitor function. <a href="#6" class="mim-tip-reference" title="Coornaert, B., Baens, M., Heyninck, K., Bekaert, T., Haegman, M., Staal, J., Sun, L., Chen, Z. J., Marynen, P., Beyaert, R. <strong>T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappa-B inhibitor A20.</strong> Nature Immun. 9: 263-271, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18223652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18223652</a>] [<a href="https://doi.org/10.1038/ni1561" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18223652">Coornaert et al. (2008)</a> concluded that A20 is a substrate of MALT1 and that MALT1 proteolytic activity is important in the fine tuning of T cell antigen receptor signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18223652" 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 immunoprecipitation, immunoblot, and FACS analysis, <a href="#9" class="mim-tip-reference" title="Ferch, U., Kloo, B., Gewies, A., Pfander, V., Duwel, M., Peschel, C., Krappmann, D., Ruland, J. <strong>Inhibition of MALT1 protease activity is selectively toxic for activated B cell-like diffuse large B cell lymphoma cells.</strong> J. Exp. Med. 206: 2313-2320, 2009. Note: Erratum: J. Exp. Med. 206: 2851 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19841089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19841089</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19841089[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20091167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19841089">Ferch et al. (2009)</a> showed that aggressive activated B cell-like (ABC) diffuse large B cell lymphoma (DLBCL) cells, but not germinal center B cell-like (GCB) DLBCL, possess constitutively assembled CARD11 (<a href="/entry/607210">607210</a>)-BCL10 (<a href="/entry/603517">603517</a>)-MALT1 (CBM) complexes that continuously and selectively process A20. Inhibition of MALT1 blocks A20 and BCL10 cleavage, reduces NFKB activity, and decreases the expression of NFKB targets BCLXL (BCL2L1; <a href="/entry/600039">600039</a>), IL6 (<a href="/entry/147620">147620</a>), and IL10 (<a href="/entry/124092">124092</a>). Inhibition of MALT1 paracaspase leads to ABC-DLBCL cell death and growth retardation. <a href="#9" class="mim-tip-reference" title="Ferch, U., Kloo, B., Gewies, A., Pfander, V., Duwel, M., Peschel, C., Krappmann, D., Ruland, J. <strong>Inhibition of MALT1 protease activity is selectively toxic for activated B cell-like diffuse large B cell lymphoma cells.</strong> J. Exp. Med. 206: 2313-2320, 2009. Note: Erratum: J. Exp. Med. 206: 2851 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19841089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19841089</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19841089[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20091167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19841089">Ferch et al. (2009)</a> concluded that MALT1 paracaspase activity has a growth-promoting role, specifically in ABC-DLBCL cells, and proposed that MALT1 protease activity is a potential target for pharmacologic treatment of ABC-DLBCL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19841089" 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="Ma, L., Zhou, Y., Zhang, Y., Li, Y., Guo, Y., He, Y., Wang, J., Lian, J., Hao, C., Moorman, J. P., Yao, Z. Q., Zhou, Y., Jia, Z. <strong>Role of A20 in interferon-alpha mediated functional restoration of myeloid dendritic cells in patients with chronic hepatitis C.</strong> Immunology 143: 670-678, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24965710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24965710</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24965710[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/10.1111/imm.12350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24965710">Ma et al. (2014)</a> observed that myeloid DCs (mDCs) isolated from patients chronically infected with hepatitis C virus (HCV; see <a href="/entry/609532">609532</a>) expressed significantly higher A20 than did mDCs from healthy individuals or from individuals who had achieved sustained virologic responses (SVRs) following antiviral treatment with IFNA (<a href="/entry/147660">147660</a>). A20 expression in mDCs from HCV-infected patients undergoing IFNA treatment was lower than in untreated patients, SVR patients, or healthy individuals. Stimulation of mDCs with polyI:C showed differences in A20 expression between HCV patients and healthy individuals, but the differences could be abrogated by IFNA treatment in vitro. Expression of A20 by polyI:C-activated mDCs negatively correlated with expression of HLA-DRA (<a href="/entry/142860">142860</a>), CD86 (<a href="/entry/601020">601020</a>), and CCR7 (<a href="/entry/600242">600242</a>), as well as with secretion of IL12 (<a href="/entry/161560">161560</a>). A20 expression positively correlated with IL10 production. Silencing of A20 increased IL12 production in mDCs of patients chronically infected with HCV. <a href="#17" class="mim-tip-reference" title="Ma, L., Zhou, Y., Zhang, Y., Li, Y., Guo, Y., He, Y., Wang, J., Lian, J., Hao, C., Moorman, J. P., Yao, Z. Q., Zhou, Y., Jia, Z. <strong>Role of A20 in interferon-alpha mediated functional restoration of myeloid dendritic cells in patients with chronic hepatitis C.</strong> Immunology 143: 670-678, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24965710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24965710</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24965710[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/10.1111/imm.12350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24965710">Ma et al. (2014)</a> proposed that A20 plays a crucial role in the negative regulation of innate immune responses during chronic viral infection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24965710" 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 genetically engineered mice bearing mutations in the A20 ovarian tumor-type deubiquitinase (OTU) domain or in the zinc finger-4 (Znf4) ubiquitin-binding motif, <a href="#26" class="mim-tip-reference" title="Wertz, I. E., Newton, K., Seshasayee, D., Kusam, S., Lam, C., Zhang, J., Popovych, N., Helgason, E., Schoeffler, A., Jeet, S., Ramamoorthi, N., Kategaya, L., and 22 others. <strong>Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation.</strong> Nature 528: 370-375, 2015. Note: Erratum: Nature 532: 402 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26649818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26649818</a>] [<a href="https://doi.org/10.1038/nature16165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26649818">Wertz et al. (2015)</a> investigated paradoxical in vitro and in vivo findings regarding the role of A20 in attenuating inflammatory signaling. <a href="#26" class="mim-tip-reference" title="Wertz, I. E., Newton, K., Seshasayee, D., Kusam, S., Lam, C., Zhang, J., Popovych, N., Helgason, E., Schoeffler, A., Jeet, S., Ramamoorthi, N., Kategaya, L., and 22 others. <strong>Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation.</strong> Nature 528: 370-375, 2015. Note: Erratum: Nature 532: 402 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26649818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26649818</a>] [<a href="https://doi.org/10.1038/nature16165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26649818">Wertz et al. (2015)</a> found that phosphorylation of A20 promotes cleavage of lys63-linked polyubiquitin chains by the OTU domain and enhances ZnF4-mediated substrate ubiquitination. Additionally, levels of linear ubiquitination dictate whether A20-deficient cells die in response to tumor necrosis factor (TNF; <a href="/entry/191160">191160</a>). Mechanistically, linear ubiquitin chains preserve the architecture of the TNFR1 (<a href="/entry/191190">191190</a>) signaling complex by blocking A20-mediated disassembly of lys63-linked polyubiquitin scaffolds. <a href="#26" class="mim-tip-reference" title="Wertz, I. E., Newton, K., Seshasayee, D., Kusam, S., Lam, C., Zhang, J., Popovych, N., Helgason, E., Schoeffler, A., Jeet, S., Ramamoorthi, N., Kategaya, L., and 22 others. <strong>Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation.</strong> Nature 528: 370-375, 2015. Note: Erratum: Nature 532: 402 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26649818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26649818</a>] [<a href="https://doi.org/10.1038/nature16165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26649818">Wertz et al. (2015)</a> concluded that collectively the studies revealed molecular mechanisms whereby A20 deubiquitinase activity and ubiquitin binding, linear ubiquitination, and cellular kinases cooperate to regulate inflammation and cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26649818" 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>Somatic Mutations</em></strong></p><p>
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Using a genomewide analysis of genetic lesions in 238 B cell lymphomas, <a href="#13" class="mim-tip-reference" title="Kato, M., Sanada, M., Kato, I., Sato, Y., Takita, J., Takeuchi, K., Niwa, A., Chen, Y., Nakazaki, K., Nomoto, J., Asakura, Y., Muto, S., and 17 others. <strong>Frequent inactivation of A20 in B-cell lymphomas.</strong> Nature 459: 712-716, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412163</a>] [<a href="https://doi.org/10.1038/nature07969" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19412163">Kato et al. (2009)</a> showed that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (see <a href="/entry/604860">604860</a>) (18 of 87; 21.8%) and Hodgkin lymphoma (see <a href="/entry/236000">236000</a>) of the nodular sclerosis histology (5 of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When reexpressed in a lymphoma-derived cell line with no functional A20 alleles, wildtype A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-kappa-B activation. The A20-deficient cells stably generated tumors in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by reexpression of A20. In A20-deficient cells, suppression of both cell growth and NF-kappa-B activity due to reexpression of A20 depended, at least partly, on cell surface receptor signaling, including the tumor necrosis factor receptor (TNFR; see <a href="/entry/191190">191190</a>). Considering the physiologic function of A20 in the negative modulation of NF-kappa-B activation induced by multiple upstream stimuli, <a href="#13" class="mim-tip-reference" title="Kato, M., Sanada, M., Kato, I., Sato, Y., Takita, J., Takeuchi, K., Niwa, A., Chen, Y., Nakazaki, K., Nomoto, J., Asakura, Y., Muto, S., and 17 others. <strong>Frequent inactivation of A20 in B-cell lymphomas.</strong> Nature 459: 712-716, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412163</a>] [<a href="https://doi.org/10.1038/nature07969" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19412163">Kato et al. (2009)</a> concluded that signaling of NF-kappa-B caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19412163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Compagno, M., Lim, W. K., Grunn, A., Nandula, S. V., Brahmachary, M., Shen, Q., Bertoni, F., Ponzoni, M., Scandurra, M., Califano, A., Bhagat, G., Chadburn, A., Dalla-Favera, R., Pasqualucci, L. <strong>Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma.</strong> Nature 459: 717-721, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412164</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19412164[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/nature07968" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19412164">Compagno et al. (2009)</a> showed that greater than 50% of activated B cell-like (ABC) diffuse large B cell lymphoma (DLBCL) and a smaller fraction of germinal center B cell-like (GCB)-DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3) and positive regulators of NF-kappa-B (see <a href="/entry/164011">164011</a>). Of these, the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NF-kappa-B responses, is most commonly affected, with approximately 30% of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumor suppressor role. <a href="#4" class="mim-tip-reference" title="Compagno, M., Lim, W. K., Grunn, A., Nandula, S. V., Brahmachary, M., Shen, Q., Bertoni, F., Ponzoni, M., Scandurra, M., Califano, A., Bhagat, G., Chadburn, A., Dalla-Favera, R., Pasqualucci, L. <strong>Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma.</strong> Nature 459: 717-721, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412164</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19412164[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/nature07968" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19412164">Compagno et al. (2009)</a> concluded that NF-kappa-B activation in DLBCL is caused by genetic lesions affecting multiple genes, the loss or activation of which may promote lymphomagenesis by leading to abnormally prolonged NF-kappa-B responses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19412164" 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>Proliferation and survival of Hodgkin and Reed/Sternberg (HRS) cells, the malignant cells of classical Hodgkin lymphoma (CHL), are dependent on constitutive activation of NFKB. By sequencing TNFAIP3 in CHL cell lines and in laser-microdissected HRS cells from CHL biopsies, <a href="#21" class="mim-tip-reference" title="Schmitz, R., Hansmann, M.-L., Bohle, V., Martin-Subero, J. I., Hartmann, S., Mechtersheimer, G., Klapper, W., Vater, I., Giefing, M., Gesk, S., Stanelle, J., Siebert, R., Kuppers, R. <strong>TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma.</strong> J. Exp. Med. 206: 981-989, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19380639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19380639</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19380639[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20090528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19380639">Schmitz et al. (2009)</a> identified somatic mutations in 16 of 36 CHL cases. The changes, which were usually biallelic, were found in 2 Epstein-Barr virus (EBV)-positive CHLs and in 14 EBV-negative CHLs. Reconstitution of wildtype TNFAIP3 in TNFAIP3-deficient CHL cell lines resulted in a significant decrease in transcripts of selected NFKB target genes and caused cytotoxicity. TNFAIP3 mutations were also found in 5 of 14 cases of primary mediastinal B-cell lymphoma (PMBL), another lymphoma marked by constitutive NFKB activity. <a href="#21" class="mim-tip-reference" title="Schmitz, R., Hansmann, M.-L., Bohle, V., Martin-Subero, J. I., Hartmann, S., Mechtersheimer, G., Klapper, W., Vater, I., Giefing, M., Gesk, S., Stanelle, J., Siebert, R., Kuppers, R. <strong>TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma.</strong> J. Exp. Med. 206: 981-989, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19380639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19380639</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19380639[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20090528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19380639">Schmitz et al. (2009)</a> concluded that TNFAIP3 is a key regulator of NFKB activity and suggested that TNFAIP3 is a novel tumor suppressor gene in CHL and PMBL. They stressed that the clustering of destructive mutations in EBV-negative CHL cases may indicate that TNFAIP3 inactivation and EBV infection/transformation may be complementing functions in CHL pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19380639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Braggio, E., Keats, J. J., Leleu, X., Van Wier, S., Jimenez-Zepeda, V. H., Valdez, R., Schop, R. F. J., Price-Troska, T., Henderson, K., Sacco, A., Azab, F., Greipp, P., and 11 others. <strong>Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappa-B signaling pathways in Waldenstrom's macroglobulinemia.</strong> Cancer Res. 69: 3579-3588, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19351844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19351844</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19351844[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/10.1158/0008-5472.CAN-08-3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19351844">Braggio et al. (2009)</a> identified biallelic inactivation of TNF receptor-associated factor-3 (TRAF3; <a href="/entry/601896">601896</a>) in 3 (5.3%) of 57 Waldenstrom macroglobulinemia (WM; see <a href="/entry/153600">153600</a>) samples. TRAF3 inactivation was associated with transcriptional activation of NF-kappa-B. In addition, 1 of 24 patients with a 6q deletion had an inactivating somatic mutation in TNFAIP3, another negative regulator of NF-kappa-B. Monoallelic deletions of chromosome 6q23, including the TNFAIP3 gene, were identified in 38% of patients, suggesting that haploinsufficiency can predispose to the development of WM. The results indicated that mutational activation of the NF-kappa-B pathway plays a role in the pathogenesis of WM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19351844" 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>Familial Behcet-Like Autoinflammatory Syndrome 1</em></strong></p><p>
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In affected members of 6 unrelated families with familial Behcet-like autoinflammatory syndrome (AIFBL1; <a href="/entry/616744">616744</a>), <a href="#29" class="mim-tip-reference" title="Zhou, Q., Wang, H., Schwartz, D. M., Stoffels, M., Park, Y. H., Zhang, Y., Yang, D., Demirkaya, E., Takeuchi, M., Tsai, W. L., Lyons, J. J., Yu, X., and 29 others. <strong>Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.</strong> Nature Genet. 48: 67-73, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26642243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26642243</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26642243[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.3459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26642243">Zhou et al. (2016)</a> identified 6 different heterozygous truncating mutations in the TNFAIP3 gene (<a href="#0001">191163.0001</a>-<a href="#0006">191163.0006</a>). The mutations in the first 2 families were found by whole-exome sequencing and confirmed by Sanger sequencing; 3 subsequent mutations were found in 3 of 150 probands with a similar disorder who were directly screened for TNFAIP3 mutations. The sixth mutation was found in 1 of 768 individuals diagnosed with Behcet disease (<a href="/entry/109650">109650</a>) who underwent targeted sequencing. In vitro functional cellular expression studies showed that all mutations failed to suppress TNF-induced NFKB (see <a href="/entry/164011">164011</a>) activity, although not in a dominant-negative fashion, which suggested haploinsufficiency as a disease mechanism. Patient cells showed reduced recruitment of TNFAIP3 to the TNFR complex (see <a href="/entry/191190">191190</a>) compared to control cells. Patient-derived cells showed increased phosphorylation of IKKA (<a href="/entry/600664">600664</a>) and IKKB (<a href="/entry/603258">603258</a>) and subsequent degradation of I-kappa-B-alpha (NFKBIA; <a href="/entry/164008">164008</a>), with nuclear translocation of the NFKB p65 subunit (RELA; <a href="/entry/164014">164014</a>) together with increased expression of NFKB-mediated proinflammatory cytokines, consistent with activation of the NFKB pathway. Cells expressing the mutant proteins showed defective removal of lys63-linked ubiquitin from TRAF6 (<a href="/entry/602355">602355</a>), NEMO (IKBKG; <a href="/entry/300248">300248</a>), and RIP1 (<a href="/entry/603453">603453</a>) after stimulation with TNF, indicating inefficient deubiquitination. Levels of proinflammatory cytokines were substantially higher in patient serum compared to controls, and showed evidence of increased IL1B (<a href="/entry/147720">147720</a>) signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26642243" 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 22 affected individuals from 9 unrelated Japanese families with AIFBL, <a href="#12" class="mim-tip-reference" title="Kadowaki, T., Ohnishi, H., Kawamoto, N., Hori, T., Nishimura, K., Kobayashi, C., Shigemura, T., Ogata, S., Inoue, Y., Kawai, T., Hiejima, E., Takagi, M., Imai, K., Nishikomori, R., Ito, S., Heike, T., Ohara, O., Morio, T., Fukao, T., Kanegane, H. <strong>Haploinsufficiency of A20 causes autoinflammatory and autoimmune disorders.</strong> J. Allergy Clin. Immun. 141: 1485-1488, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29241730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29241730</a>] [<a href="https://doi.org/10.1016/j.jaci.2017.10.039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29241730">Kadowaki et al. (2018)</a> identified heterozygous mutations in the TNFAIP3 gene (see, e.g., <a href="#0007">191163.0007</a>). There were 5 frameshift mutations, 2 splice site mutation, 1 nonsense mutation, and 1 missense variant, suggesting haploinsufficiency as the pathogenetic mechanism. Western blot analysis of cells carrying the mutations showed that the nonsense and frameshift mutations, but not the C243Y missense variant, caused decreased protein levels compared to controls. In vitro functional expression assays using a luciferase reporter showed that the nonsense and frameshift mutations, but not the C243Y missense variant, resulted in increased NFKB gene activity compared to wildtype, consistent with defective TNFAIP3 function. The authors postulated haploinsufficiency of A20 as the pathogenetic disease mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29241730" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 13-year-old Chinese boy with AIFBL, <a href="#8" class="mim-tip-reference" title="Dong, X., Liu, L., Wang, Y., Yang, X., Wang, W., Lin, L., Sun, B., Hou, J., Ying, W., Hui, X., Zhou, Q., Liu, D., Yao, H., Sun, J., Wang, X. <strong>Novel heterogeneous mutation of TNFAIP3 in a Chinese patient with Behcet-like phenotype and persistent EBV viremia.</strong> J. Clin. Immun. 39: 188-194, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30810840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30810840</a>] [<a href="https://doi.org/10.1007/s10875-019-00604-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30810840">Dong et al. (2019)</a> identified a heterozygous missense variant in the TNFAIP3 gene (M476I; <a href="#0008">191163.0008</a>). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not present in public databases. The mutation was inherited from the patient's mother who had milder symptoms, consistent with variable penetrance and expressivity. Patient cells showed decreased TNFAIP3 mRNA and protein levels after stimulation with LPS compared to controls. Patient cells also showed increased activation of the NFKB1 (<a href="/entry/164011">164011</a>) signaling pathway compared to controls, even without stimulation. Furthermore, both the patient and his mother had significantly increased levels of TNF (<a href="/entry/191160">191160</a>) compared to controls, consistent with the phenotype of autoinflammation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30810840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 27-year-old man of Ashkenazi Jewish descent with AIFBL, <a href="#10" class="mim-tip-reference" title="Gans, M. D., Wang, H., Moura, N. S., Aksentijevich, I., Rubinstein, A. <strong>A20 haploinsufficiency presenting with a combined immunodeficiency.</strong> J. Clin. Immun. 40: 1041-1044, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32666380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32666380</a>] [<a href="https://doi.org/10.1007/s10875-020-00823-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32666380">Gans et al. (2020)</a> identified a heterozygous frameshift mutation in the TNFAIP3 gene (<a href="#0009">191163.0009</a>). The mutation, which was found by whole-exome sequencing, was not present in population databases. The mutation occurred in the N-terminal ovarian tumor domain. Familial segregation studies and functional studies of the variant were not performed, but it was predicted to cause haploinsufficiency of TNFAIP3. In addition to autoinflammation and autoimmunity, the patient had features of a primary combined immunodeficiency, thus expanding the phenotype associated with TNFAIP3 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32666380" 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>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between systemic lupus erythematosus and variation in the TNFAIP3 gene, see <a href="/entry/612378">612378</a>.</p>
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<p><a href="#14" class="mim-tip-reference" title="Lee, E. G., Boone, D. L., Chai, S., Libby, S. L., Chien, M., Lodolce, J. P., Ma, A. <strong>Failure to regulate TNF-induced NF-kappa-B and cell death responses in A20-deficient mice.</strong> Science 289: 2350-2354, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11009421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11009421</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11009421[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.289.5488.2350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11009421">Lee et al. (2000)</a> generated A20-deficient mice by targeted disruption. A20 +/- mice appeared normal without evidence of pathology. A20 -/- mice, born from interbred A20 +/- mice in mendelian ratios, developed runting as early as 1 week of age. Mice deficient for A20 developed severe inflammation and cachexia, were hypersensitive to both lipopolysaccharide and TNF (<a href="/entry/191160">191160</a>), and died prematurely. A20-deficient cells failed to terminate TNF-induced NFKB (see <a href="/entry/164011">164011</a>) responses. These cells were also more susceptible than control cells to undergo TNF-mediated program cell death. Thus, A20 is critical for limiting inflammation by terminating TNF-induced NFKB responses in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11009421" 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 mice doubly deficient in either A20 and Tnf or A20 and Tnfr1 (<a href="/entry/191190">191190</a>), <a href="#2" class="mim-tip-reference" title="Boone, D. L., Turer, E. E., Lee, E. G., Ahmad, R.-C., Wheeler, M. T., Tsui, C., Hurley, P., Chien, M., Chai, S., Hitotsumatsu, O., McNally, E., Pickart, C., Ma, A. <strong>The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses.</strong> Nature Immun. 5: 1052-1060, 2004. Note: Erratum: Nature Immun. 5: 114 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15334086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15334086</a>] [<a href="https://doi.org/10.1038/ni1110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15334086">Boone et al. (2004)</a> showed that, in addition to terminating TNF-induced signals, A20 is required for terminating TLR (e.g., TLR4, <a href="/entry/603030">603030</a>)-induced activity of NFKB. Mutation and immunoblot analyses indicated that A20 acts, via its conserved OTU-like domain, as a deubiquitinating enzyme on ubiquitinated TRAF6 (<a href="/entry/602355">602355</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15334086" 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 mice subjected to aortic banding, <a href="#5" class="mim-tip-reference" title="Cook, S. A., Novikov, M. S., Ahn, Y., Matsui, T., Rosenweig, A. <strong>A20 is dynamically regulated in the heart and inhibits the hypertrophic response.</strong> Circulation 108: 664-667, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12900338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12900338</a>] [<a href="https://doi.org/10.1161/01.CIR.0000086978.95976.41" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12900338">Cook et al. (2003)</a> detected greater than 4-fold A20 upregulation (p less than 0.05) at 3 hours, coinciding with peak NFKB activation. A20 was also upregulated in cultured neonatal cardiomyocytes stimulated with phenylephrine or endothelin-1 (EDN1; <a href="/entry/131240">131240</a>) (2.8-fold and 4-fold, respectively; p less than 0.05), again paralleling NFKB activation. Cardiomyocytes infected with an adenoviral vector (Ad) encoding A20 inhibited TNF-stimulated NFKB signaling with an efficacy comparable to dominant-negative inhibitor of kappa-B kinase-beta (IKBKB; <a href="/entry/603258">603258</a>). Ad-IKBKB-infected cardiomyocytes exhibited increased apoptosis when serum-starved or subjected to hypoxia-reoxygenation, whereas Ad-A20-infected cardiomyocytes did not. Expression of Ad-A20 inhibited the hypertrophic response in cardiomyocytes stimulated with phenylephrine or endothelin-1 (<a href="/entry/131240">131240</a>). <a href="#5" class="mim-tip-reference" title="Cook, S. A., Novikov, M. S., Ahn, Y., Matsui, T., Rosenweig, A. <strong>A20 is dynamically regulated in the heart and inhibits the hypertrophic response.</strong> Circulation 108: 664-667, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12900338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12900338</a>] [<a href="https://doi.org/10.1161/01.CIR.0000086978.95976.41" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12900338">Cook et al. (2003)</a> concluded that A20 is dynamically regulated during acute biomechanical stress in the heart and functions to attenuate cardiac hypertrophy through the inhibition of NFKB signaling without sensitizing cardiomyocytes to apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12900338" 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="#28" class="mim-tip-reference" title="Wolfrum, S., Teupser, D., Tan, M., Chen, K. Y., Breslow, J. L. <strong>The protective effect of A20 on atherosclerosis in apolipoprotein E-deficient mice is associated with reduced expression of NF-kappa-B target genes.</strong> Proc. Nat. Acad. Sci. 104: 18601-18606, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18006655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18006655</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18006655[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0709011104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18006655">Wolfrum et al. (2007)</a> found that ApoE (<a href="/entry/107741">107741</a>) -/- mice that were haploinsufficient for A20 developed larger atherosclerotic lesions than ApoE -/- mice with normal A20 expression. The larger lesions were associated with increased expression of the NF-kappa-B target genes Vcam1 (<a href="/entry/192225">192225</a>), Icam1 (<a href="/entry/147840">147840</a>), and Mcsf (CSF1; <a href="/entry/120420">120420</a>) and increased plasma levels of NF-kappa-B-regulated cytokines. In contrast, overexpression of A20 resulted in smaller lesions. <a href="#28" class="mim-tip-reference" title="Wolfrum, S., Teupser, D., Tan, M., Chen, K. Y., Breslow, J. L. <strong>The protective effect of A20 on atherosclerosis in apolipoprotein E-deficient mice is associated with reduced expression of NF-kappa-B target genes.</strong> Proc. Nat. Acad. Sci. 104: 18601-18606, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18006655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18006655</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18006655[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0709011104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18006655">Wolfrum et al. (2007)</a> concluded that A20, acting mainly through NF-kappa-B, influences atherosclerosis susceptibility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18006655" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Matmati, M., Jacques, P., Maelfait, J., Verheugen, E., Kool, M., Sze, M., Geboes, L., Louagie, E., McGuire, C., Vereecke, L., Chu, Y., Boon, L., Staelens, S., Matthys, P., Lambrecht, B. N., Schmidt-Supprian, M., Pasparakis, M., Elewaut, D., Beyaert, R., van Loo, G. <strong>A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis.</strong> Nature Genet. 43: 908-912, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21841782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21841782</a>] [<a href="https://doi.org/10.1038/ng.874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21841782">Matmati et al. (2011)</a> showed that specific ablation of TNFAIP3 in myeloid cells results in spontaneous development of a severe destructive polyarthritis with many features of rheumatoid arthritis (<a href="/entry/180300">180300</a>). Myeloid-A20-deficient mice had high levels of inflammatory cytokines in their serum, consistent with a sustained NF-kappa-B activation and higher TNF production by macrophages. Destructive polyarthritis in myeloid A20 knockout mice was TLR4-MyD88 (<a href="/entry/602170">602170</a>) and IL6 (<a href="/entry/147620">147620</a>)-dependent but was TNF independent. Myeloid A20 deficiency also promoted osteoclastogenesis in mice. <a href="#18" class="mim-tip-reference" title="Matmati, M., Jacques, P., Maelfait, J., Verheugen, E., Kool, M., Sze, M., Geboes, L., Louagie, E., McGuire, C., Vereecke, L., Chu, Y., Boon, L., Staelens, S., Matthys, P., Lambrecht, B. N., Schmidt-Supprian, M., Pasparakis, M., Elewaut, D., Beyaert, R., van Loo, G. <strong>A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis.</strong> Nature Genet. 43: 908-912, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21841782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21841782</a>] [<a href="https://doi.org/10.1038/ng.874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21841782">Matmati et al. (2011)</a> concluded that, taken together, their observations revealed a critical and cell-specific function for A20 in the etiology of rheumatoid arthritis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21841782" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Lu, T. T., Onizawa, M., Hammer, G. E., Turer, E. E., Yin, Q., Damko, E., Agelidis, A., Shifrin, N., Advincula, R., Barrera, J., Malynn, B. A., Wu, H., Ma, A. <strong>Dimerization and ubiquitin mediated recruitment of A20, a complex deubiquitinating enzyme.</strong> Immunity 38: 896-905, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23602765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23602765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23602765[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.immuni.2013.03.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23602765">Lu et al. (2013)</a> generated 2 lines of gene-targeted mice by abrogating either the deubiquitinating activity of A20 (Tnfaip3-OTU mice) or zinc finger-4 of A20 (Tnfaip3-ZF4 mice). Both strains exhibited increased responses to Tnf and sensitivity to colitis. The deubiquitinating motif restricted both lys48- and lys63-linked ubiquitination of Rip1. ZF4 was required for recruitment of A20 to ubiquitinated Rip1. The 2 mutant A20 proteins complemented each other through dimerization to regulate Rip1 ubiquitination and Nfkb signaling in compound mutant Tnfaip3-OTU/Tnfaip3-ZF4 cells. <a href="#16" class="mim-tip-reference" title="Lu, T. T., Onizawa, M., Hammer, G. E., Turer, E. E., Yin, Q., Damko, E., Agelidis, A., Shifrin, N., Advincula, R., Barrera, J., Malynn, B. A., Wu, H., Ma, A. <strong>Dimerization and ubiquitin mediated recruitment of A20, a complex deubiquitinating enzyme.</strong> Immunity 38: 896-905, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23602765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23602765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23602765[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.immuni.2013.03.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23602765">Lu et al. (2013)</a> concluded that A20 proteins collaborate to restrict TNF signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23602765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Vande Walle, L., Van Opdenbosch, N., Jacques, P., Fossoul, A., Verheugen, E., Vogel, P., Beyaert, R., Elewaut, D., Kanneganti, T.-D., van Loo, G., Lamkanfi, M. <strong>Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis.</strong> Nature 512: 69-73, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25043000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25043000</a>] [<a href="https://doi.org/10.1038/nature13322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25043000">Vande Walle et al. (2014)</a> showed that rheumatoid arthritis in A20 myeloid cell-specific knockout mice (A20(myel-KO); <a href="#18" class="mim-tip-reference" title="Matmati, M., Jacques, P., Maelfait, J., Verheugen, E., Kool, M., Sze, M., Geboes, L., Louagie, E., McGuire, C., Vereecke, L., Chu, Y., Boon, L., Staelens, S., Matthys, P., Lambrecht, B. N., Schmidt-Supprian, M., Pasparakis, M., Elewaut, D., Beyaert, R., van Loo, G. <strong>A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis.</strong> Nature Genet. 43: 908-912, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21841782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21841782</a>] [<a href="https://doi.org/10.1038/ng.874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21841782">Matmati et al., 2011</a>) relies on the Nlrp3 inflammasome and Il1 receptor (IL1R; <a href="/entry/147810">147810</a>) signaling. Macrophages lacking A20 have increased basal and lipopolysaccharide-induced expression levels of the inflammasome adaptor Nlrp3 and pro-Il1b (<a href="/entry/147720">147720</a>). As a result, A20 deficiency in macrophages significantly enhances Nlrp3 inflammasome-mediated caspase-1 (CASP1; <a href="/entry/147678">147678</a>) activation, pyroptosis, and Il1B secretion by soluble and crystalline Nlrp3 stimuli. In contrast, activation of the Nlrc4 (<a href="/entry/606831">606831</a>) and Aim2 (<a href="/entry/604578">604578</a>) inflammasomes is not altered. Importantly, increased Nlrp3 inflammasome activation contributes to the pathology of rheumatoid arthritis in vivo, since deletion of Nlrp3, Casp1, and the Il1 receptor markedly protects against rheumatoid arthritis-associated inflammation and cartilage destruction in A20(myel-KO) mice. <a href="#24" class="mim-tip-reference" title="Vande Walle, L., Van Opdenbosch, N., Jacques, P., Fossoul, A., Verheugen, E., Vogel, P., Beyaert, R., Elewaut, D., Kanneganti, T.-D., van Loo, G., Lamkanfi, M. <strong>Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis.</strong> Nature 512: 69-73, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25043000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25043000</a>] [<a href="https://doi.org/10.1038/nature13322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25043000">Vande Walle et al. (2014)</a> concluded that these results revealed A20 as a novel negative regulator of NLRP3 inflammasome activation, and described A20(myel-KO) mice as the first experimental model to study the role of inflammasomes in the pathology of rheumatoid arthritis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25043000+21841782" 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>Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS; see <a href="/entry/126200">126200</a>). In both EAE and MS, autoreactive T cells infiltrate the central nervous system (CNS) and mediate an inflammatory response that causes demyelination and axon degradation. <a href="#15" class="mim-tip-reference" title="Liu, X., He, F., Pang, R., Zhao, D., Qiu, W., Shan, K., Zhang, J., Lu, Y., Li, Y., Wang, Y. <strong>Interleukin-17 (IL-17)-induced microRNA 873 (miR-873) contributes to the pathogenesis of experimental autoimmune encephalomyelitis by targeting A20 ubiquitin-editing enzyme.</strong> J. Biol. Chem. 289: 28971-28986, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25183005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25183005</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25183005[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.M114.577429" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25183005">Liu et al. (2014)</a> found that expression of A20 was downregulated in EAE and in primary mouse astrocytes stimulated with IL17 (see <a href="/entry/603149">603149</a>). Expression profiling revealed that expression of microRNA-873 (MIR873; <a href="/entry/616137">616137</a>) was upregulated in EAE and activated astrocytes. <a href="#15" class="mim-tip-reference" title="Liu, X., He, F., Pang, R., Zhao, D., Qiu, W., Shan, K., Zhang, J., Lu, Y., Li, Y., Wang, Y. <strong>Interleukin-17 (IL-17)-induced microRNA 873 (miR-873) contributes to the pathogenesis of experimental autoimmune encephalomyelitis by targeting A20 ubiquitin-editing enzyme.</strong> J. Biol. Chem. 289: 28971-28986, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25183005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25183005</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25183005[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.M114.577429" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25183005">Liu et al. (2014)</a> identified an Mir873 target sequence in the 3-prime UTR of an A20 transcript. Overexpression and reporter gene assays revealed that Mir873 facilitated production of inflammatory cytokines and chemokines in astrocytes stimulated with IL17 by directly downregulating expression of A20 and indirectly promoting NF-kappa-B (see NFKB1, <a href="/entry/164011">164011</a>) activation. Use of an miRNA sponge that lowered Mir873 content reduced production of cytokines in activated astrocytes and ameliorated CNS damage in EAE mice. Silencing of A20 exacerbated the effect of Mir873 in activated astrocytes and increased demyelination in EAE mice. <a href="#15" class="mim-tip-reference" title="Liu, X., He, F., Pang, R., Zhao, D., Qiu, W., Shan, K., Zhang, J., Lu, Y., Li, Y., Wang, Y. <strong>Interleukin-17 (IL-17)-induced microRNA 873 (miR-873) contributes to the pathogenesis of experimental autoimmune encephalomyelitis by targeting A20 ubiquitin-editing enzyme.</strong> J. Biol. Chem. 289: 28971-28986, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25183005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25183005</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25183005[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.M114.577429" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25183005">Liu et al. (2014)</a> concluded that upregulation of MIR873 and downregulation of A20 contribute to inflammatory damage in MS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25183005" 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=191163[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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<p>In 3 affected members of a European Canadian family with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; <a href="/entry/616744">616744</a>), <a href="#29" class="mim-tip-reference" title="Zhou, Q., Wang, H., Schwartz, D. M., Stoffels, M., Park, Y. H., Zhang, Y., Yang, D., Demirkaya, E., Takeuchi, M., Tsai, W. L., Lyons, J. J., Yu, X., and 29 others. <strong>Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.</strong> Nature Genet. 48: 67-73, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26642243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26642243</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26642243[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.3459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26642243">Zhou et al. (2016)</a> identified a heterozygous c.680T-A transversion (c.680T-A, NM_006290.2) in exon 5 of the TNFAIP3 gene, resulting in a leu227-to-ter (L227X) substitution in the OTU domain, which mediates the deubiquitinase activity. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Patient cells had decreased TNFAIP3 protein levels with no detectable mutant protein, suggesting that the mutant protein undergoes degradation. Overexpressed mutant protein failed to suppress TNF (<a href="/entry/191160">191160</a>)-induced NFKB (see <a href="/entry/164011">164011</a>) activity in transfected HEK293T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26642243" 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">rs864321682 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864321682;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=rs864321682" 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=rs864321682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 affected members of a European American family with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; <a href="/entry/616744">616744</a>), <a href="#29" class="mim-tip-reference" title="Zhou, Q., Wang, H., Schwartz, D. M., Stoffels, M., Park, Y. H., Zhang, Y., Yang, D., Demirkaya, E., Takeuchi, M., Tsai, W. L., Lyons, J. J., Yu, X., and 29 others. <strong>Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.</strong> Nature Genet. 48: 67-73, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26642243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26642243</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26642243[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.3459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26642243">Zhou et al. (2016)</a> identified a heterozygous 1-bp deletion (c.671delT, NM_006290.2) in exon 5 of the TNFAIP3 gene, resulting in a frameshift and premature termination (Phe224SerfsTer4) in the OTU domain, which mediates the deubiquitinase activity. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Patient cells had decreased TNFAIP3 protein levels with no detectable mutant protein, suggesting that the mutant protein undergoes degradation. Overexpressed mutant protein failed to suppress TNF (<a href="/entry/191160">191160</a>)-induced NFKB (see <a href="/entry/164011">164011</a>) activity in transfected HEK293T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26642243" 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">rs864321626 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864321626;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=rs864321626" 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=rs864321626" 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=RCV000579071 OR RCV002508767" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000579071, RCV002508767" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000579071...</a>
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<p>In a Turkish father and son with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; <a href="/entry/616744">616744</a>), <a href="#29" class="mim-tip-reference" title="Zhou, Q., Wang, H., Schwartz, D. M., Stoffels, M., Park, Y. H., Zhang, Y., Yang, D., Demirkaya, E., Takeuchi, M., Tsai, W. L., Lyons, J. J., Yu, X., and 29 others. <strong>Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.</strong> Nature Genet. 48: 67-73, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26642243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26642243</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26642243[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.3459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26642243">Zhou et al. (2016)</a> identified a heterozygous c.811C-T transition (c.811C-T, NM_006290.2) in exon 6 of the TNFAIP3 gene, resulting in an arg271-to-ter (R271X) substitution in the OTU domain, which mediates the deubiquitinase activity. The mutation segregated with the disorder in the family and was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Overexpressed mutant protein failed to suppress TNF (<a href="/entry/191160">191160</a>)-induced NFKB (see <a href="/entry/164011">164011</a>) activity in transfected HEK293T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26642243" 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">rs864321683 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864321683;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=rs864321683" 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=rs864321683" 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 woman with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; <a href="/entry/616744">616744</a>), <a href="#29" class="mim-tip-reference" title="Zhou, Q., Wang, H., Schwartz, D. M., Stoffels, M., Park, Y. H., Zhang, Y., Yang, D., Demirkaya, E., Takeuchi, M., Tsai, W. L., Lyons, J. J., Yu, X., and 29 others. <strong>Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.</strong> Nature Genet. 48: 67-73, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26642243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26642243</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26642243[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.3459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26642243">Zhou et al. (2016)</a> identified a de novo heterozygous 1-bp deletion (c.1809delG, NM_006290.2) in exon 7 of the TNFAIP3 gene, resulting in a frameshift and premature termination (Thr604ArgfsTer93) in the ZnF4 domain, which is essential for ubiquitin ligase activity and dimerization. The mutation was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Overexpressed mutant protein failed to suppress TNF (<a href="/entry/191160">191160</a>)-induced NFKB (see <a href="/entry/164011">164011</a>) activity in transfected HEK293T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26642243" 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">rs864321684 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864321684;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=rs864321684" 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=rs864321684" 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 Dutch mother and daughter with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; <a href="/entry/616744">616744</a>), <a href="#29" class="mim-tip-reference" title="Zhou, Q., Wang, H., Schwartz, D. M., Stoffels, M., Park, Y. H., Zhang, Y., Yang, D., Demirkaya, E., Takeuchi, M., Tsai, W. L., Lyons, J. J., Yu, X., and 29 others. <strong>Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.</strong> Nature Genet. 48: 67-73, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26642243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26642243</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26642243[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.3459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26642243">Zhou et al. (2016)</a> identified a heterozygous c.918C-G transversion (c.918C-G, NM_006290.2) in exon 6 of the TNFAIP3 gene, resulting in a tyr306-to-ter (Y306X) substitution in the OTU domain, which mediates the deubiquitinase activity. The mutation was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Overexpressed mutant protein failed to suppress TNF (<a href="/entry/191160">191160</a>)-induced NFKB (see <a href="/entry/164011">164011</a>) activity in transfected HEK293T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26642243" 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">rs864321685 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864321685;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=rs864321685" 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=rs864321685" 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 Turkish mother and her 2 daughters with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; <a href="/entry/616744">616744</a>), <a href="#29" class="mim-tip-reference" title="Zhou, Q., Wang, H., Schwartz, D. M., Stoffels, M., Park, Y. H., Zhang, Y., Yang, D., Demirkaya, E., Takeuchi, M., Tsai, W. L., Lyons, J. J., Yu, X., and 29 others. <strong>Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.</strong> Nature Genet. 48: 67-73, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26642243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26642243</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26642243[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.3459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26642243">Zhou et al. (2016)</a> identified a heterozygous 1-bp deletion (c.799delG, NM_006290.2) in exon 5 of the TNFAIP3 gene, resulting in a frameshift and premature termination (Pro268LeufsTer19) in the OTU domain, which mediates the deubiquitinase activity. The mutation was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Overexpressed mutant protein failed to suppress TNF (<a href="/entry/191160">191160</a>)-induced NFKB (see <a href="/entry/164011">164011</a>) activity in transfected HEK293T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26642243" 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">rs2114499761 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2114499761;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=rs2114499761" 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=rs2114499761" 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 mother and daughter (P18 and P17) from a Japanese family (family 6) with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; <a href="/entry/616744">616744</a>), <a href="#12" class="mim-tip-reference" title="Kadowaki, T., Ohnishi, H., Kawamoto, N., Hori, T., Nishimura, K., Kobayashi, C., Shigemura, T., Ogata, S., Inoue, Y., Kawai, T., Hiejima, E., Takagi, M., Imai, K., Nishikomori, R., Ito, S., Heike, T., Ohara, O., Morio, T., Fukao, T., Kanegane, H. <strong>Haploinsufficiency of A20 causes autoinflammatory and autoimmune disorders.</strong> J. Allergy Clin. Immun. 141: 1485-1488, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29241730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29241730</a>] [<a href="https://doi.org/10.1016/j.jaci.2017.10.039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29241730">Kadowaki et al. (2018)</a> identified a heterozygous 1-bp deletion (c.1345delA) in the TNFAIP3 gene, resulting in a frameshift and premature termination (Asn449ThrfsTer28). Western blot analysis of cells with the mutation showed mildly decreased TNFAIP3 protein levels compared to wildtype. In vitro functional expression assays in HEK293 cells using a luciferase reporter showed that the mutation resulted in increased NFKB (<a href="/entry/164011">164011</a>) gene activity compared to wildtype, consistent with defective TNFAIP3 function. P17 was a 7-year-old girl with periodic fevers and aphthous stomatitis since infancy. She also had a developmental disorder. Her mother had stomatitis from childhood, abdominal pain and fever since the teenage years, and genital ulcers, resulting in a diagnosis of Behcet disease. Three additional maternal family members who were not genotyped had Behcet-like symptoms, consistent with autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29241730" 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=RCV002508823" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002508823" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002508823</a>
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<p>In a 13-year-old Chinese boy with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; <a href="/entry/616744">616744</a>), <a href="#8" class="mim-tip-reference" title="Dong, X., Liu, L., Wang, Y., Yang, X., Wang, W., Lin, L., Sun, B., Hou, J., Ying, W., Hui, X., Zhou, Q., Liu, D., Yao, H., Sun, J., Wang, X. <strong>Novel heterogeneous mutation of TNFAIP3 in a Chinese patient with Behcet-like phenotype and persistent EBV viremia.</strong> J. Clin. Immun. 39: 188-194, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30810840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30810840</a>] [<a href="https://doi.org/10.1007/s10875-019-00604-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30810840">Dong et al. (2019)</a> identified a heterozygous c.1428G-A transition in the TNFAIP3 gene, resulting in a met476-to-ile (M476I) substitution in the zinc finger 2 domain (ZF2). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not present in public databases. The mutation was inherited from the patient's mother who had milder symptoms, consistent with variable penetrance and expressivity. Patient cells showed decreased TNFAIP3 mRNA and protein levels after stimulation with LPS compared to controls. Patient cells also showed increased activation of the NFKB1 (<a href="/entry/164011">164011</a>) signaling pathway compared to controls, even without stimulation. Furthermore, both the patient and his mother had significantly increased levels of TNF (<a href="/entry/191160">191160</a>) compared to controls, consistent with the phenotype of autoinflammation. The patient presented with a history of recurrent fever, lymphadenopathy, skin rash, arthritis, and multiple recurrent oral and gastrointestinal ulcerations. He also had recurrent tonsillitis, persistent EBV viremia, and variable lymphocyte abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30810840" 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 AUTOINFLAMMATORY SYNDROME, FAMILIAL, BEHCET-LIKE 1</strong>
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TNFAIP3, 1-BP DEL, NT912
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1776278098 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1776278098;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=rs1776278098" 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=rs1776278098" 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=RCV001037789 OR RCV002508792" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001037789, RCV002508792" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001037789...</a>
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<p>In a 27-year-old man of Ashkenazi Jewish descent with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; <a href="/entry/616744">616744</a>), <a href="#10" class="mim-tip-reference" title="Gans, M. D., Wang, H., Moura, N. S., Aksentijevich, I., Rubinstein, A. <strong>A20 haploinsufficiency presenting with a combined immunodeficiency.</strong> J. Clin. Immun. 40: 1041-1044, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32666380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32666380</a>] [<a href="https://doi.org/10.1007/s10875-020-00823-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32666380">Gans et al. (2020)</a> identified a heterozygous 1-bp deletion (c.912del, NM_001270507) in exon 6 of the TNFAIP2 gene, predicted to result in a frameshift and premature termination (Glu305SerfsTer3). The mutation, which was found by whole-exome sequencing, was not present in population databases. The mutation occurred in the N-terminal ovarian tumor domain. Functional studies of the variant were not performed, but it was consistent with haploinsufficiency of TNFAIP3. The patient had recurrent fevers, mouth ulcers, and chronic diarrhea since childhood, consistent with autoinflammation and autoimmunity, but he also had recurrent infections and EBV viremia, suggesting a primary immunodeficiency. Laboratory studies showed hypogammaglobulinemia, low B, T, and NK cells, and impaired T-cell proliferation. There were increased serum levels of inflammatory markers and activation of the NFKB (see <a href="/entry/164011">164011</a>) signaling pathway with increased expression of interferon response genes. This case report expanded the immune dysregulation phenotype associated with TNFAIP3 mutations to include combined immunodeficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32666380" 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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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="Aeschlimann2018" class="mim-anchor"></a>
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Aeschlimann, F. A., Batu, E. D., Canna, S. W., Go, E., Gul, A., Hoffmann, P., Leavis, H. L., Ozen, S., Schwartz, D. M., Stone, D. L., van Royen-Kerkof, A., Kastner, D. L., Aksentijevich, I., Laxer, R. M.
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<strong>A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease.</strong>
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Ann. Rheum. Dis. 77: 728-735, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29317407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29317407</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29317407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/annrheumdis-2017-212403" target="_blank">Full Text</a>]
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Boone, D. L., Turer, E. E., Lee, E. G., Ahmad, R.-C., Wheeler, M. T., Tsui, C., Hurley, P., Chien, M., Chai, S., Hitotsumatsu, O., McNally, E., Pickart, C., Ma, A.
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<strong>The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses.</strong>
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Nature Immun. 5: 1052-1060, 2004. Note: Erratum: Nature Immun. 5: 114 only, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15334086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15334086</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15334086" 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/ni1110" target="_blank">Full Text</a>]
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Braggio, E., Keats, J. J., Leleu, X., Van Wier, S., Jimenez-Zepeda, V. H., Valdez, R., Schop, R. F. J., Price-Troska, T., Henderson, K., Sacco, A., Azab, F., Greipp, P., and 11 others.
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<strong>Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappa-B signaling pathways in Waldenstrom's macroglobulinemia.</strong>
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Cancer Res. 69: 3579-3588, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19351844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19351844</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19351844[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=19351844" 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/10.1158/0008-5472.CAN-08-3701" target="_blank">Full Text</a>]
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Compagno, M., Lim, W. K., Grunn, A., Nandula, S. V., Brahmachary, M., Shen, Q., Bertoni, F., Ponzoni, M., Scandurra, M., Califano, A., Bhagat, G., Chadburn, A., Dalla-Favera, R., Pasqualucci, L.
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<strong>Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma.</strong>
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Nature 459: 717-721, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19412164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19412164</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19412164[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=19412164" 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/nature07968" target="_blank">Full Text</a>]
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Cook, S. A., Novikov, M. S., Ahn, Y., Matsui, T., Rosenweig, A.
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<strong>A20 is dynamically regulated in the heart and inhibits the hypertrophic response.</strong>
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Circulation 108: 664-667, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12900338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12900338</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12900338" 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/10.1161/01.CIR.0000086978.95976.41" target="_blank">Full Text</a>]
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Coornaert, B., Baens, M., Heyninck, K., Bekaert, T., Haegman, M., Staal, J., Sun, L., Chen, Z. J., Marynen, P., Beyaert, R.
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Nature Immun. 9: 263-271, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18223652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18223652</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18223652" 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/ni1561" target="_blank">Full Text</a>]
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Dixit, V. M., Green, S., Sarma, V., Holzman, L. B., Wolf, F. W., O'Rourke, K., Ward, P. A., Prochownik, E. V., Marks, R. M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2406243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2406243</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2406243" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Dong, X., Liu, L., Wang, Y., Yang, X., Wang, W., Lin, L., Sun, B., Hou, J., Ying, W., Hui, X., Zhou, Q., Liu, D., Yao, H., Sun, J., Wang, X.
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<strong>Novel heterogeneous mutation of TNFAIP3 in a Chinese patient with Behcet-like phenotype and persistent EBV viremia.</strong>
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J. Clin. Immun. 39: 188-194, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30810840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30810840</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30810840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10875-019-00604-9" target="_blank">Full Text</a>]
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Ferch, U., Kloo, B., Gewies, A., Pfander, V., Duwel, M., Peschel, C., Krappmann, D., Ruland, J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19841089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19841089</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19841089[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=19841089" 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/10.1084/jem.20091167" target="_blank">Full Text</a>]
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<a id="Gans2020" class="mim-anchor"></a>
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Gans, M. D., Wang, H., Moura, N. S., Aksentijevich, I., Rubinstein, A.
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<strong>A20 haploinsufficiency presenting with a combined immunodeficiency.</strong>
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J. Clin. Immun. 40: 1041-1044, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32666380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32666380</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32666380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10875-020-00823-5" target="_blank">Full Text</a>]
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<a id="27" class="mim-anchor"></a>
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<a id="Wertz2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wertz, I. E., O'Rourke, K. M., Zhou, H., Eby, M., Aravind, L., Seshagiri, S., Wu, P., Wiesmann, C., Baker, R., Boone, D. L., Ma, A., Koonin, E. V., Dixit, V. M.
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<strong>De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappa-B signalling.</strong>
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Nature 430: 694-699, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15258597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15258597</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15258597" 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/nature02794" target="_blank">Full Text</a>]
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<a id="28" class="mim-anchor"></a>
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<a id="Wolfrum2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wolfrum, S., Teupser, D., Tan, M., Chen, K. Y., Breslow, J. L.
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<strong>The protective effect of A20 on atherosclerosis in apolipoprotein E-deficient mice is associated with reduced expression of NF-kappa-B target genes.</strong>
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Proc. Nat. Acad. Sci. 104: 18601-18606, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18006655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18006655</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18006655[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=18006655" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0709011104" target="_blank">Full Text</a>]
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<a id="29" class="mim-anchor"></a>
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<a id="Zhou2016" class="mim-anchor"></a>
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<p class="mim-text-font">
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Zhou, Q., Wang, H., Schwartz, D. M., Stoffels, M., Park, Y. H., Zhang, Y., Yang, D., Demirkaya, E., Takeuchi, M., Tsai, W. L., Lyons, J. J., Yu, X., and 29 others.
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<strong>Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.</strong>
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Nature Genet. 48: 67-73, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26642243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26642243</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26642243[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=26642243" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.3459" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 03/29/2022
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Ada Hamosh - updated : 02/04/2016<br>Cassandra L. Kniffin - updated : 1/12/2016<br>Paul J. Converse - updated : 4/30/2015<br>Patricia A. Hartz - updated : 12/15/2014<br>Ada Hamosh - updated : 10/2/2014<br>Paul J. Converse - updated : 11/15/2013<br>Ada Hamosh - updated : 10/7/2011<br>Ada Hamosh - updated : 9/8/2011<br>Paul J. Converse - updated : 8/3/2010<br>Ada Hamosh - updated : 3/9/2010<br>Cassandra L. Kniffin - updated : 1/15/2010<br>Paul J. Converse - updated : 10/15/2009<br>Ada Hamosh - updated : 6/16/2009<br>Paul J. Converse - updated : 7/15/2008<br>Patricia A. Hartz - updated : 5/27/2008<br>Patricia A. Hartz - updated : 2/8/2008<br>Paul J. Converse - updated : 12/14/2006<br>Paul J. Converse - updated : 11/9/2005<br>Marla J. F. O'Neill - updated : 10/22/2004<br>Ada Hamosh - updated : 9/13/2004<br>Ada Hamosh - updated : 10/20/2000
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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Creation Date:
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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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Victor A. McKusick : 6/23/1993
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<span class="mim-text-font">
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alopez : 03/20/2023
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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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alopez : 04/08/2022<br>alopez : 04/07/2022<br>ckniffin : 03/29/2022<br>carol : 04/22/2019<br>alopez : 08/03/2016<br>alopez : 02/04/2016<br>carol : 1/14/2016<br>carol : 1/14/2016<br>alopez : 1/13/2016<br>ckniffin : 1/12/2016<br>mgross : 5/7/2015<br>mgross : 5/7/2015<br>mcolton : 4/30/2015<br>mgross : 12/15/2014<br>mcolton : 12/15/2014<br>alopez : 10/2/2014<br>mgross : 11/22/2013<br>mcolton : 11/15/2013<br>mgross : 11/26/2012<br>terry : 11/19/2012<br>terry : 7/27/2012<br>alopez : 10/18/2011<br>terry : 10/7/2011<br>alopez : 9/13/2011<br>terry : 9/8/2011<br>alopez : 8/5/2010<br>terry : 8/3/2010<br>terry : 8/3/2010<br>terry : 8/3/2010<br>alopez : 3/11/2010<br>alopez : 3/11/2010<br>alopez : 3/11/2010<br>terry : 3/9/2010<br>wwang : 1/15/2010<br>ckniffin : 12/22/2009<br>wwang : 12/9/2009<br>mgross : 11/11/2009<br>terry : 10/15/2009<br>alopez : 6/17/2009<br>terry : 6/16/2009<br>mgross : 7/15/2008<br>mgross : 6/23/2008<br>terry : 5/27/2008<br>mgross : 2/12/2008<br>mgross : 2/12/2008<br>terry : 2/8/2008<br>mgross : 1/28/2008<br>mgross : 12/20/2006<br>terry : 12/14/2006<br>mgross : 11/9/2005<br>carol : 10/22/2004<br>terry : 10/22/2004<br>alopez : 9/15/2004<br>terry : 9/13/2004<br>alopez : 10/20/2000<br>terry : 10/20/2000<br>carol : 3/17/1999<br>psherman : 11/19/1998<br>carol : 6/23/1993
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<strong>*</strong> 191163
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<h3>
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<span class="mim-font">
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TUMOR NECROSIS FACTOR-ALPHA-INDUCED PROTEIN 3; TNFAIP3
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</h3>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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A20<br />
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OTU DOMAIN-CONTAINING PROTEIN 7C; OTUD7C
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TNFAIP3</em></strong>
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<strong>
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<em>
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Cytogenetic location: 6q23.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 6:137,866,349-137,883,312 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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6q23.3
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<span class="mim-font">
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Autoinflammatory syndrome, familial, Behcet-like 1
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<span class="mim-font">
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616744
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The TNFAIP3 gene encodes an ubiquitin-editing enzyme with a critical function in the inhibition of key proinflammatory molecules to negatively regulate inflammation and the immune response (summary by Aeschlimann et al., 2018). </p><p>A20 is a cytoplasmic zinc finger protein that inhibits nuclear factor kappa-B (NFKB; see 164011) activity and tumor necrosis factor (TNF; 191160)-mediated programmed cell death. TNF dramatically increases A20 mRNA expression in all tissues (Dixit et al., 1990; Lee et al., 2000). </p>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<p>Cytokines such as TNF profoundly affect endothelial cell function, promoting, for example, interaction with leukocytes and inducing a procoagulant phenotype. Changes of this nature are likely to be central to the proinflammatory effects of TNF. Dixit et al. (1990) analyzed TNF-induced primary response genes in human umbilical vein endothelial cells. Of the 6 induced cDNAs identified, 2 encoded paracrine factors, neutrophil chemotactic factor (146930) and monocyte chemotactic factor (158105); 1 encoded a membrane receptor for neutrophils, endothelial leukocyte adhesion molecule 1 (ELAM1; 131210); and 3 encoded hitherto undescribed TNF primary response genes. On exposure of endothelial cells to TNF, there was a rapid and substantial increase in the levels of mRNA encoding the 6 genes, which were further superinduced by cycloheximide. Thus these represent primary response genes, as their induction does not depend on protein synthesis. One of the 3 new proteins, designated A20, was found on sequence analysis to code for a novel zinc finger protein (Opipari et al., 1990). </p>
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>Hartz (2014) mapped the TNFAIP3 gene to chromosome 6q23.3 based on an alignment of the TNFAIP3 sequence (GenBank AL157444) with the genomic sequence (GRCh38).</p><p>Wolfrum et al. (2007) stated that the mouse Tnfaip3 gene maps to proximal chromosome 10. </p>
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<div>
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<br />
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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 class="mim-text-font">
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<p>O'Reilly and Moynagh (2003) expressed A20 and TLR4 (603030) in a human embryonic kidney cell line and observed inhibition of NFKB activation after LPS stimulation. Mutation analysis showed that the C-terminal zinc finger domain of A20 was sufficient for NFKB inhibition, whereas the full-length protein was required for inhibition of AP1 (165160) activation and for induction of IL8 (146930). O'Reilly and Moynagh (2003) concluded that A20 modulates TLR4 signaling at or downstream of MEKK1 (MAP3K1; 600982). </p><p>Wertz et al. (2004) demonstrated that A20 downregulates NF-kappa-B signaling through the cooperative activity of its 2 ubiquitin-editing domains. The N-terminal domain of A20, which is a deubiquitinating enzyme of the OTU (ovarian tumor) family, removes lysine-63-linked ubiquitin chains from receptor-interacting protein (RIP; 603453), an essential mediator of the proximal TNF receptor-1 (TNFR1; 191190) signaling complex. The C-terminal domain of A20, composed of 7 C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with lysine-48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation. Wertz et al. (2004) defined a novel ubiquitin ligase domain and identified 2 sequential mechanisms by which A20 downregulates NF-kappa-B signaling. They also provided an example of a protein containing separate ubiquitin ligase and deubiquitinating domains, both of which participate in mediating a distinct regulatory effect. </p><p>Vendrell et al. (2007) found that expression of A20 was downregulated by estradiol treatment of an estrogen receptor (ER; see 133430)-positive, hormone-responsive human breast cancer cell line. Conversely, A20 was highly expressed in ER-negative cell lines. Overexpression of A20 in MCF7 breast cancer cells conferred resistance to tamoxifen-induced cytotoxicity that was associated with dysregulation of BAX (600040), BCL2 (151430), BAK (600516), phospho-BAD (603167), and several cyclins (e.g., CCNA2; 123835). A20 was overexpressed in tamoxifen-resistant cell lines, and high A20 expression was also observed in more aggressive breast tumors. Vendrell et al. (2007) concluded that A20 is a key protein involved in tamoxifen resistance. </p><p>Song et al. (2008) found that silencing of A20 allowed mouse dendritic cells (DCs) to hyperactivate cytotoxic lymphocytes and T-helper cells and inhibit regulatory T cells (Tregs), enhancing infiltration of tumor-infiltrating lymphocytes into tumors. They proposed that the inhibitory effects of A20-silenced DCs on Tregs may tip the balance from immune suppression to antitumor immunity. </p><p>Shembade et al. (2010) showed that A20 inhibits the E3 ligase activities of TRAF6 (602355), TRAF2 (601895), and cIAP1 (601712) by antagonizing interactions with E2 ubiquitin-conjugating enzymes UBC13 (603679) and UBCH5C (602963). A20, together with the regulatory molecule TAX1BP1 (605326), interacted with UBC13 and UBCH5C and triggered their ubiquitination and proteasome-dependent degradation. These findings suggested a mechanism of A20 action in the inhibition of inflammatory signaling pathways. </p><p>By immunoblot analysis, Coornaert et al. (2008) showed that MALT1 (604860) is a functional cysteine protease activated by T cell receptor stimulation and that it rapidly cleaves A20 after arg439, impairing its NFKB (see 164011) inhibitor function. Coornaert et al. (2008) concluded that A20 is a substrate of MALT1 and that MALT1 proteolytic activity is important in the fine tuning of T cell antigen receptor signaling. </p><p>Using immunoprecipitation, immunoblot, and FACS analysis, Ferch et al. (2009) showed that aggressive activated B cell-like (ABC) diffuse large B cell lymphoma (DLBCL) cells, but not germinal center B cell-like (GCB) DLBCL, possess constitutively assembled CARD11 (607210)-BCL10 (603517)-MALT1 (CBM) complexes that continuously and selectively process A20. Inhibition of MALT1 blocks A20 and BCL10 cleavage, reduces NFKB activity, and decreases the expression of NFKB targets BCLXL (BCL2L1; 600039), IL6 (147620), and IL10 (124092). Inhibition of MALT1 paracaspase leads to ABC-DLBCL cell death and growth retardation. Ferch et al. (2009) concluded that MALT1 paracaspase activity has a growth-promoting role, specifically in ABC-DLBCL cells, and proposed that MALT1 protease activity is a potential target for pharmacologic treatment of ABC-DLBCL. </p><p>Ma et al. (2014) observed that myeloid DCs (mDCs) isolated from patients chronically infected with hepatitis C virus (HCV; see 609532) expressed significantly higher A20 than did mDCs from healthy individuals or from individuals who had achieved sustained virologic responses (SVRs) following antiviral treatment with IFNA (147660). A20 expression in mDCs from HCV-infected patients undergoing IFNA treatment was lower than in untreated patients, SVR patients, or healthy individuals. Stimulation of mDCs with polyI:C showed differences in A20 expression between HCV patients and healthy individuals, but the differences could be abrogated by IFNA treatment in vitro. Expression of A20 by polyI:C-activated mDCs negatively correlated with expression of HLA-DRA (142860), CD86 (601020), and CCR7 (600242), as well as with secretion of IL12 (161560). A20 expression positively correlated with IL10 production. Silencing of A20 increased IL12 production in mDCs of patients chronically infected with HCV. Ma et al. (2014) proposed that A20 plays a crucial role in the negative regulation of innate immune responses during chronic viral infection. </p><p>Using genetically engineered mice bearing mutations in the A20 ovarian tumor-type deubiquitinase (OTU) domain or in the zinc finger-4 (Znf4) ubiquitin-binding motif, Wertz et al. (2015) investigated paradoxical in vitro and in vivo findings regarding the role of A20 in attenuating inflammatory signaling. Wertz et al. (2015) found that phosphorylation of A20 promotes cleavage of lys63-linked polyubiquitin chains by the OTU domain and enhances ZnF4-mediated substrate ubiquitination. Additionally, levels of linear ubiquitination dictate whether A20-deficient cells die in response to tumor necrosis factor (TNF; 191160). Mechanistically, linear ubiquitin chains preserve the architecture of the TNFR1 (191190) signaling complex by blocking A20-mediated disassembly of lys63-linked polyubiquitin scaffolds. Wertz et al. (2015) concluded that collectively the studies revealed molecular mechanisms whereby A20 deubiquitinase activity and ubiquitin binding, linear ubiquitination, and cellular kinases cooperate to regulate inflammation and cell death. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Somatic Mutations</em></strong></p><p>
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Using a genomewide analysis of genetic lesions in 238 B cell lymphomas, Kato et al. (2009) showed that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (see 604860) (18 of 87; 21.8%) and Hodgkin lymphoma (see 236000) of the nodular sclerosis histology (5 of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When reexpressed in a lymphoma-derived cell line with no functional A20 alleles, wildtype A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-kappa-B activation. The A20-deficient cells stably generated tumors in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by reexpression of A20. In A20-deficient cells, suppression of both cell growth and NF-kappa-B activity due to reexpression of A20 depended, at least partly, on cell surface receptor signaling, including the tumor necrosis factor receptor (TNFR; see 191190). Considering the physiologic function of A20 in the negative modulation of NF-kappa-B activation induced by multiple upstream stimuli, Kato et al. (2009) concluded that signaling of NF-kappa-B caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas. </p><p>Compagno et al. (2009) showed that greater than 50% of activated B cell-like (ABC) diffuse large B cell lymphoma (DLBCL) and a smaller fraction of germinal center B cell-like (GCB)-DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3) and positive regulators of NF-kappa-B (see 164011). Of these, the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NF-kappa-B responses, is most commonly affected, with approximately 30% of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumor suppressor role. Compagno et al. (2009) concluded that NF-kappa-B activation in DLBCL is caused by genetic lesions affecting multiple genes, the loss or activation of which may promote lymphomagenesis by leading to abnormally prolonged NF-kappa-B responses. </p><p>Proliferation and survival of Hodgkin and Reed/Sternberg (HRS) cells, the malignant cells of classical Hodgkin lymphoma (CHL), are dependent on constitutive activation of NFKB. By sequencing TNFAIP3 in CHL cell lines and in laser-microdissected HRS cells from CHL biopsies, Schmitz et al. (2009) identified somatic mutations in 16 of 36 CHL cases. The changes, which were usually biallelic, were found in 2 Epstein-Barr virus (EBV)-positive CHLs and in 14 EBV-negative CHLs. Reconstitution of wildtype TNFAIP3 in TNFAIP3-deficient CHL cell lines resulted in a significant decrease in transcripts of selected NFKB target genes and caused cytotoxicity. TNFAIP3 mutations were also found in 5 of 14 cases of primary mediastinal B-cell lymphoma (PMBL), another lymphoma marked by constitutive NFKB activity. Schmitz et al. (2009) concluded that TNFAIP3 is a key regulator of NFKB activity and suggested that TNFAIP3 is a novel tumor suppressor gene in CHL and PMBL. They stressed that the clustering of destructive mutations in EBV-negative CHL cases may indicate that TNFAIP3 inactivation and EBV infection/transformation may be complementing functions in CHL pathogenesis. </p><p>Braggio et al. (2009) identified biallelic inactivation of TNF receptor-associated factor-3 (TRAF3; 601896) in 3 (5.3%) of 57 Waldenstrom macroglobulinemia (WM; see 153600) samples. TRAF3 inactivation was associated with transcriptional activation of NF-kappa-B. In addition, 1 of 24 patients with a 6q deletion had an inactivating somatic mutation in TNFAIP3, another negative regulator of NF-kappa-B. Monoallelic deletions of chromosome 6q23, including the TNFAIP3 gene, were identified in 38% of patients, suggesting that haploinsufficiency can predispose to the development of WM. The results indicated that mutational activation of the NF-kappa-B pathway plays a role in the pathogenesis of WM. </p><p><strong><em>Familial Behcet-Like Autoinflammatory Syndrome 1</em></strong></p><p>
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In affected members of 6 unrelated families with familial Behcet-like autoinflammatory syndrome (AIFBL1; 616744), Zhou et al. (2016) identified 6 different heterozygous truncating mutations in the TNFAIP3 gene (191163.0001-191163.0006). The mutations in the first 2 families were found by whole-exome sequencing and confirmed by Sanger sequencing; 3 subsequent mutations were found in 3 of 150 probands with a similar disorder who were directly screened for TNFAIP3 mutations. The sixth mutation was found in 1 of 768 individuals diagnosed with Behcet disease (109650) who underwent targeted sequencing. In vitro functional cellular expression studies showed that all mutations failed to suppress TNF-induced NFKB (see 164011) activity, although not in a dominant-negative fashion, which suggested haploinsufficiency as a disease mechanism. Patient cells showed reduced recruitment of TNFAIP3 to the TNFR complex (see 191190) compared to control cells. Patient-derived cells showed increased phosphorylation of IKKA (600664) and IKKB (603258) and subsequent degradation of I-kappa-B-alpha (NFKBIA; 164008), with nuclear translocation of the NFKB p65 subunit (RELA; 164014) together with increased expression of NFKB-mediated proinflammatory cytokines, consistent with activation of the NFKB pathway. Cells expressing the mutant proteins showed defective removal of lys63-linked ubiquitin from TRAF6 (602355), NEMO (IKBKG; 300248), and RIP1 (603453) after stimulation with TNF, indicating inefficient deubiquitination. Levels of proinflammatory cytokines were substantially higher in patient serum compared to controls, and showed evidence of increased IL1B (147720) signaling. </p><p>In 22 affected individuals from 9 unrelated Japanese families with AIFBL, Kadowaki et al. (2018) identified heterozygous mutations in the TNFAIP3 gene (see, e.g., 191163.0007). There were 5 frameshift mutations, 2 splice site mutation, 1 nonsense mutation, and 1 missense variant, suggesting haploinsufficiency as the pathogenetic mechanism. Western blot analysis of cells carrying the mutations showed that the nonsense and frameshift mutations, but not the C243Y missense variant, caused decreased protein levels compared to controls. In vitro functional expression assays using a luciferase reporter showed that the nonsense and frameshift mutations, but not the C243Y missense variant, resulted in increased NFKB gene activity compared to wildtype, consistent with defective TNFAIP3 function. The authors postulated haploinsufficiency of A20 as the pathogenetic disease mechanism. </p><p>In a 13-year-old Chinese boy with AIFBL, Dong et al. (2019) identified a heterozygous missense variant in the TNFAIP3 gene (M476I; 191163.0008). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not present in public databases. The mutation was inherited from the patient's mother who had milder symptoms, consistent with variable penetrance and expressivity. Patient cells showed decreased TNFAIP3 mRNA and protein levels after stimulation with LPS compared to controls. Patient cells also showed increased activation of the NFKB1 (164011) signaling pathway compared to controls, even without stimulation. Furthermore, both the patient and his mother had significantly increased levels of TNF (191160) compared to controls, consistent with the phenotype of autoinflammation. </p><p>In a 27-year-old man of Ashkenazi Jewish descent with AIFBL, Gans et al. (2020) identified a heterozygous frameshift mutation in the TNFAIP3 gene (191163.0009). The mutation, which was found by whole-exome sequencing, was not present in population databases. The mutation occurred in the N-terminal ovarian tumor domain. Familial segregation studies and functional studies of the variant were not performed, but it was predicted to cause haploinsufficiency of TNFAIP3. In addition to autoinflammation and autoimmunity, the patient had features of a primary combined immunodeficiency, thus expanding the phenotype associated with TNFAIP3 mutations. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between systemic lupus erythematosus and variation in the TNFAIP3 gene, see 612378.</p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lee et al. (2000) generated A20-deficient mice by targeted disruption. A20 +/- mice appeared normal without evidence of pathology. A20 -/- mice, born from interbred A20 +/- mice in mendelian ratios, developed runting as early as 1 week of age. Mice deficient for A20 developed severe inflammation and cachexia, were hypersensitive to both lipopolysaccharide and TNF (191160), and died prematurely. A20-deficient cells failed to terminate TNF-induced NFKB (see 164011) responses. These cells were also more susceptible than control cells to undergo TNF-mediated program cell death. Thus, A20 is critical for limiting inflammation by terminating TNF-induced NFKB responses in vivo. </p><p>Using mice doubly deficient in either A20 and Tnf or A20 and Tnfr1 (191190), Boone et al. (2004) showed that, in addition to terminating TNF-induced signals, A20 is required for terminating TLR (e.g., TLR4, 603030)-induced activity of NFKB. Mutation and immunoblot analyses indicated that A20 acts, via its conserved OTU-like domain, as a deubiquitinating enzyme on ubiquitinated TRAF6 (602355). </p><p>In mice subjected to aortic banding, Cook et al. (2003) detected greater than 4-fold A20 upregulation (p less than 0.05) at 3 hours, coinciding with peak NFKB activation. A20 was also upregulated in cultured neonatal cardiomyocytes stimulated with phenylephrine or endothelin-1 (EDN1; 131240) (2.8-fold and 4-fold, respectively; p less than 0.05), again paralleling NFKB activation. Cardiomyocytes infected with an adenoviral vector (Ad) encoding A20 inhibited TNF-stimulated NFKB signaling with an efficacy comparable to dominant-negative inhibitor of kappa-B kinase-beta (IKBKB; 603258). Ad-IKBKB-infected cardiomyocytes exhibited increased apoptosis when serum-starved or subjected to hypoxia-reoxygenation, whereas Ad-A20-infected cardiomyocytes did not. Expression of Ad-A20 inhibited the hypertrophic response in cardiomyocytes stimulated with phenylephrine or endothelin-1 (131240). Cook et al. (2003) concluded that A20 is dynamically regulated during acute biomechanical stress in the heart and functions to attenuate cardiac hypertrophy through the inhibition of NFKB signaling without sensitizing cardiomyocytes to apoptosis. </p><p>Wolfrum et al. (2007) found that ApoE (107741) -/- mice that were haploinsufficient for A20 developed larger atherosclerotic lesions than ApoE -/- mice with normal A20 expression. The larger lesions were associated with increased expression of the NF-kappa-B target genes Vcam1 (192225), Icam1 (147840), and Mcsf (CSF1; 120420) and increased plasma levels of NF-kappa-B-regulated cytokines. In contrast, overexpression of A20 resulted in smaller lesions. Wolfrum et al. (2007) concluded that A20, acting mainly through NF-kappa-B, influences atherosclerosis susceptibility. </p><p>Matmati et al. (2011) showed that specific ablation of TNFAIP3 in myeloid cells results in spontaneous development of a severe destructive polyarthritis with many features of rheumatoid arthritis (180300). Myeloid-A20-deficient mice had high levels of inflammatory cytokines in their serum, consistent with a sustained NF-kappa-B activation and higher TNF production by macrophages. Destructive polyarthritis in myeloid A20 knockout mice was TLR4-MyD88 (602170) and IL6 (147620)-dependent but was TNF independent. Myeloid A20 deficiency also promoted osteoclastogenesis in mice. Matmati et al. (2011) concluded that, taken together, their observations revealed a critical and cell-specific function for A20 in the etiology of rheumatoid arthritis. </p><p>Lu et al. (2013) generated 2 lines of gene-targeted mice by abrogating either the deubiquitinating activity of A20 (Tnfaip3-OTU mice) or zinc finger-4 of A20 (Tnfaip3-ZF4 mice). Both strains exhibited increased responses to Tnf and sensitivity to colitis. The deubiquitinating motif restricted both lys48- and lys63-linked ubiquitination of Rip1. ZF4 was required for recruitment of A20 to ubiquitinated Rip1. The 2 mutant A20 proteins complemented each other through dimerization to regulate Rip1 ubiquitination and Nfkb signaling in compound mutant Tnfaip3-OTU/Tnfaip3-ZF4 cells. Lu et al. (2013) concluded that A20 proteins collaborate to restrict TNF signaling. </p><p>Vande Walle et al. (2014) showed that rheumatoid arthritis in A20 myeloid cell-specific knockout mice (A20(myel-KO); Matmati et al., 2011) relies on the Nlrp3 inflammasome and Il1 receptor (IL1R; 147810) signaling. Macrophages lacking A20 have increased basal and lipopolysaccharide-induced expression levels of the inflammasome adaptor Nlrp3 and pro-Il1b (147720). As a result, A20 deficiency in macrophages significantly enhances Nlrp3 inflammasome-mediated caspase-1 (CASP1; 147678) activation, pyroptosis, and Il1B secretion by soluble and crystalline Nlrp3 stimuli. In contrast, activation of the Nlrc4 (606831) and Aim2 (604578) inflammasomes is not altered. Importantly, increased Nlrp3 inflammasome activation contributes to the pathology of rheumatoid arthritis in vivo, since deletion of Nlrp3, Casp1, and the Il1 receptor markedly protects against rheumatoid arthritis-associated inflammation and cartilage destruction in A20(myel-KO) mice. Vande Walle et al. (2014) concluded that these results revealed A20 as a novel negative regulator of NLRP3 inflammasome activation, and described A20(myel-KO) mice as the first experimental model to study the role of inflammasomes in the pathology of rheumatoid arthritis. </p><p>Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS; see 126200). In both EAE and MS, autoreactive T cells infiltrate the central nervous system (CNS) and mediate an inflammatory response that causes demyelination and axon degradation. Liu et al. (2014) found that expression of A20 was downregulated in EAE and in primary mouse astrocytes stimulated with IL17 (see 603149). Expression profiling revealed that expression of microRNA-873 (MIR873; 616137) was upregulated in EAE and activated astrocytes. Liu et al. (2014) identified an Mir873 target sequence in the 3-prime UTR of an A20 transcript. Overexpression and reporter gene assays revealed that Mir873 facilitated production of inflammatory cytokines and chemokines in astrocytes stimulated with IL17 by directly downregulating expression of A20 and indirectly promoting NF-kappa-B (see NFKB1, 164011) activation. Use of an miRNA sponge that lowered Mir873 content reduced production of cytokines in activated astrocytes and ameliorated CNS damage in EAE mice. Silencing of A20 exacerbated the effect of Mir873 in activated astrocytes and increased demyelination in EAE mice. Liu et al. (2014) concluded that upregulation of MIR873 and downregulation of A20 contribute to inflammatory damage in MS. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>9 Selected Examples):</strong>
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</h4>
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<p />
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 AUTOINFLAMMATORY SYNDROME, FAMILIAL, BEHCET-LIKE 1</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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TNFAIP3, LEU227TER
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<br />
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SNP: rs864321625,
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ClinVar: RCV002508765
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</span>
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<span class="mim-text-font">
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<p>In 3 affected members of a European Canadian family with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Zhou et al. (2016) identified a heterozygous c.680T-A transversion (c.680T-A, NM_006290.2) in exon 5 of the TNFAIP3 gene, resulting in a leu227-to-ter (L227X) substitution in the OTU domain, which mediates the deubiquitinase activity. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Patient cells had decreased TNFAIP3 protein levels with no detectable mutant protein, suggesting that the mutant protein undergoes degradation. Overexpressed mutant protein failed to suppress TNF (191160)-induced NFKB (see 164011) activity in transfected HEK293T cells. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 AUTOINFLAMMATORY SYNDROME, FAMILIAL, BEHCET-LIKE 1</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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TNFAIP3, 1-BP DEL, 671T
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<br />
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SNP: rs864321682,
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ClinVar: RCV002508766
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</span>
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<div>
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<span class="mim-text-font">
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<p>In 3 affected members of a European American family with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Zhou et al. (2016) identified a heterozygous 1-bp deletion (c.671delT, NM_006290.2) in exon 5 of the TNFAIP3 gene, resulting in a frameshift and premature termination (Phe224SerfsTer4) in the OTU domain, which mediates the deubiquitinase activity. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Patient cells had decreased TNFAIP3 protein levels with no detectable mutant protein, suggesting that the mutant protein undergoes degradation. Overexpressed mutant protein failed to suppress TNF (191160)-induced NFKB (see 164011) activity in transfected HEK293T cells. </p>
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</span>
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<div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 AUTOINFLAMMATORY SYNDROME, FAMILIAL, BEHCET-LIKE 1</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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TNFAIP3, ARG271TER
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<br />
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SNP: rs864321626,
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ClinVar: RCV000579071, RCV002508767
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<span class="mim-text-font">
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<p>In a Turkish father and son with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Zhou et al. (2016) identified a heterozygous c.811C-T transition (c.811C-T, NM_006290.2) in exon 6 of the TNFAIP3 gene, resulting in an arg271-to-ter (R271X) substitution in the OTU domain, which mediates the deubiquitinase activity. The mutation segregated with the disorder in the family and was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Overexpressed mutant protein failed to suppress TNF (191160)-induced NFKB (see 164011) activity in transfected HEK293T cells. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>.0004 AUTOINFLAMMATORY SYNDROME, FAMILIAL, BEHCET-LIKE 1</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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TNFAIP3, 1-BP DEL, 1809G
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<br />
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SNP: rs864321683,
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ClinVar: RCV001853276, RCV002508768
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a woman with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Zhou et al. (2016) identified a de novo heterozygous 1-bp deletion (c.1809delG, NM_006290.2) in exon 7 of the TNFAIP3 gene, resulting in a frameshift and premature termination (Thr604ArgfsTer93) in the ZnF4 domain, which is essential for ubiquitin ligase activity and dimerization. The mutation was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Overexpressed mutant protein failed to suppress TNF (191160)-induced NFKB (see 164011) activity in transfected HEK293T cells. </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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<h4>
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<span class="mim-font">
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<strong>.0005 AUTOINFLAMMATORY SYNDROME, FAMILIAL, BEHCET-LIKE 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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TNFAIP3, TYR306TER
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<br />
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SNP: rs864321684,
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ClinVar: RCV002508769
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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 Dutch mother and daughter with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Zhou et al. (2016) identified a heterozygous c.918C-G transversion (c.918C-G, NM_006290.2) in exon 6 of the TNFAIP3 gene, resulting in a tyr306-to-ter (Y306X) substitution in the OTU domain, which mediates the deubiquitinase activity. The mutation was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Overexpressed mutant protein failed to suppress TNF (191160)-induced NFKB (see 164011) activity in transfected HEK293T cells. </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 AUTOINFLAMMATORY SYNDROME, FAMILIAL, BEHCET-LIKE 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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TNFAIP3, 1-BP DEL, 799G
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<br />
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SNP: rs864321685,
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ClinVar: RCV002508770
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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 Turkish mother and her 2 daughters with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Zhou et al. (2016) identified a heterozygous 1-bp deletion (c.799delG, NM_006290.2) in exon 5 of the TNFAIP3 gene, resulting in a frameshift and premature termination (Pro268LeufsTer19) in the OTU domain, which mediates the deubiquitinase activity. The mutation was not found in the dbSNP or ExAC databases, or in 500 in-house control exomes. Overexpressed mutant protein failed to suppress TNF (191160)-induced NFKB (see 164011) activity in transfected HEK293T cells. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 AUTOINFLAMMATORY SYNDROME, FAMILIAL, BEHCET-LIKE 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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TNFAIP3, 1-BP DEL, 1345A
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<br />
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SNP: rs2114499761,
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ClinVar: RCV002508822
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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 mother and daughter (P18 and P17) from a Japanese family (family 6) with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Kadowaki et al. (2018) identified a heterozygous 1-bp deletion (c.1345delA) in the TNFAIP3 gene, resulting in a frameshift and premature termination (Asn449ThrfsTer28). Western blot analysis of cells with the mutation showed mildly decreased TNFAIP3 protein levels compared to wildtype. In vitro functional expression assays in HEK293 cells using a luciferase reporter showed that the mutation resulted in increased NFKB (164011) gene activity compared to wildtype, consistent with defective TNFAIP3 function. P17 was a 7-year-old girl with periodic fevers and aphthous stomatitis since infancy. She also had a developmental disorder. Her mother had stomatitis from childhood, abdominal pain and fever since the teenage years, and genital ulcers, resulting in a diagnosis of Behcet disease. Three additional maternal family members who were not genotyped had Behcet-like symptoms, consistent with autosomal dominant inheritance. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0008 AUTOINFLAMMATORY SYNDROME, FAMILIAL, BEHCET-LIKE 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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TNFAIP3, MET476ILE
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<br />
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SNP: rs2114500822,
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ClinVar: RCV002508823
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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 13-year-old Chinese boy with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Dong et al. (2019) identified a heterozygous c.1428G-A transition in the TNFAIP3 gene, resulting in a met476-to-ile (M476I) substitution in the zinc finger 2 domain (ZF2). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not present in public databases. The mutation was inherited from the patient's mother who had milder symptoms, consistent with variable penetrance and expressivity. Patient cells showed decreased TNFAIP3 mRNA and protein levels after stimulation with LPS compared to controls. Patient cells also showed increased activation of the NFKB1 (164011) signaling pathway compared to controls, even without stimulation. Furthermore, both the patient and his mother had significantly increased levels of TNF (191160) compared to controls, consistent with the phenotype of autoinflammation. The patient presented with a history of recurrent fever, lymphadenopathy, skin rash, arthritis, and multiple recurrent oral and gastrointestinal ulcerations. He also had recurrent tonsillitis, persistent EBV viremia, and variable lymphocyte abnormalities. </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>.0009 AUTOINFLAMMATORY SYNDROME, FAMILIAL, BEHCET-LIKE 1</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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TNFAIP3, 1-BP DEL, NT912
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<br />
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SNP: rs1776278098,
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ClinVar: RCV001037789, RCV002508792
|
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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 27-year-old man of Ashkenazi Jewish descent with familial Behcet-like autoinflammatory syndrome-1 (AIFBL1; 616744), Gans et al. (2020) identified a heterozygous 1-bp deletion (c.912del, NM_001270507) in exon 6 of the TNFAIP2 gene, predicted to result in a frameshift and premature termination (Glu305SerfsTer3). The mutation, which was found by whole-exome sequencing, was not present in population databases. The mutation occurred in the N-terminal ovarian tumor domain. Functional studies of the variant were not performed, but it was consistent with haploinsufficiency of TNFAIP3. The patient had recurrent fevers, mouth ulcers, and chronic diarrhea since childhood, consistent with autoinflammation and autoimmunity, but he also had recurrent infections and EBV viremia, suggesting a primary immunodeficiency. Laboratory studies showed hypogammaglobulinemia, low B, T, and NK cells, and impaired T-cell proliferation. There were increased serum levels of inflammatory markers and activation of the NFKB (see 164011) signaling pathway with increased expression of interferon response genes. This case report expanded the immune dysregulation phenotype associated with TNFAIP3 mutations to include combined immunodeficiency. </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>REFERENCES</strong>
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|
</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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Aeschlimann, F. A., Batu, E. D., Canna, S. W., Go, E., Gul, A., Hoffmann, P., Leavis, H. L., Ozen, S., Schwartz, D. M., Stone, D. L., van Royen-Kerkof, A., Kastner, D. L., Aksentijevich, I., Laxer, R. M.
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<strong>A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease.</strong>
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Ann. Rheum. Dis. 77: 728-735, 2018.
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Boone, D. L., Turer, E. E., Lee, E. G., Ahmad, R.-C., Wheeler, M. T., Tsui, C., Hurley, P., Chien, M., Chai, S., Hitotsumatsu, O., McNally, E., Pickart, C., Ma, A.
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<strong>The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses.</strong>
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Nature Immun. 5: 1052-1060, 2004. Note: Erratum: Nature Immun. 5: 114 only, 2005.
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Braggio, E., Keats, J. J., Leleu, X., Van Wier, S., Jimenez-Zepeda, V. H., Valdez, R., Schop, R. F. J., Price-Troska, T., Henderson, K., Sacco, A., Azab, F., Greipp, P., and 11 others.
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<strong>Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappa-B signaling pathways in Waldenstrom's macroglobulinemia.</strong>
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Compagno, M., Lim, W. K., Grunn, A., Nandula, S. V., Brahmachary, M., Shen, Q., Bertoni, F., Ponzoni, M., Scandurra, M., Califano, A., Bhagat, G., Chadburn, A., Dalla-Favera, R., Pasqualucci, L.
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<strong>Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma.</strong>
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Cook, S. A., Novikov, M. S., Ahn, Y., Matsui, T., Rosenweig, A.
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<strong>A20 is dynamically regulated in the heart and inhibits the hypertrophic response.</strong>
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Dong, X., Liu, L., Wang, Y., Yang, X., Wang, W., Lin, L., Sun, B., Hou, J., Ying, W., Hui, X., Zhou, Q., Liu, D., Yao, H., Sun, J., Wang, X.
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Liu, X., He, F., Pang, R., Zhao, D., Qiu, W., Shan, K., Zhang, J., Lu, Y., Li, Y., Wang, Y.
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<p class="mim-text-font">
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Lu, T. T., Onizawa, M., Hammer, G. E., Turer, E. E., Yin, Q., Damko, E., Agelidis, A., Shifrin, N., Advincula, R., Barrera, J., Malynn, B. A., Wu, H., Ma, A.
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<strong>Dimerization and ubiquitin mediated recruitment of A20, a complex deubiquitinating enzyme.</strong>
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Immunity 38: 896-905, 2013.
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[PubMed: 23602765]
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[Full Text: https://doi.org/10.1016/j.immuni.2013.03.008]
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<p class="mim-text-font">
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Ma, L., Zhou, Y., Zhang, Y., Li, Y., Guo, Y., He, Y., Wang, J., Lian, J., Hao, C., Moorman, J. P., Yao, Z. Q., Zhou, Y., Jia, Z.
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|
<strong>Role of A20 in interferon-alpha mediated functional restoration of myeloid dendritic cells in patients with chronic hepatitis C.</strong>
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|
Immunology 143: 670-678, 2014.
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[PubMed: 24965710]
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[Full Text: https://doi.org/10.1111/imm.12350]
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</p>
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<li>
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<p class="mim-text-font">
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<p class="mim-text-font">
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Opipari, A. W., Jr., Boguski, M. S., Dixit, V. M.
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<strong>The A20 cDNA induced by tumor necrosis factor-alpha encodes a novel type of zinc finger protein.</strong>
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Schmitz, R., Hansmann, M.-L., Bohle, V., Martin-Subero, J. I., Hartmann, S., Mechtersheimer, G., Klapper, W., Vater, I., Giefing, M., Gesk, S., Stanelle, J., Siebert, R., Kuppers, R.
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Shembade, N., Ma, A., Harhaj, E. W.
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<strong>Inhibition of NF-kappa-B signaling by A20 through disruption of ubiquitin enzyme complexes.</strong>
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Science 327: 1135-1139, 2010.
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[PubMed: 20185725]
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Song, X.-T., Evel-Kabler, K., Shen, L., Rollins, L., Huang, X. F., Chen, S.-Y.
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<strong>A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression.</strong>
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Nature Med. 14: 258-265, 2008.
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[PubMed: 18311150]
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Vande Walle, L., Van Opdenbosch, N., Jacques, P., Fossoul, A., Verheugen, E., Vogel, P., Beyaert, R., Elewaut, D., Kanneganti, T.-D., van Loo, G., Lamkanfi, M.
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<strong>Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis.</strong>
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Nature 512: 69-73, 2014.
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[PubMed: 25043000]
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Vendrell, J. A., Ghayad, S., Ben-Larbi, S., Dumontet, C., Mechti, N., Cohen, P. A.
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<strong>A20/TNFAIP3, a new estrogen-regulated gene that confers tamoxifen resistance in breast cancer cells.</strong>
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Oncogene 26: 4656-4667, 2007.
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[PubMed: 17297453]
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Wertz, I. E., Newton, K., Seshasayee, D., Kusam, S., Lam, C., Zhang, J., Popovych, N., Helgason, E., Schoeffler, A., Jeet, S., Ramamoorthi, N., Kategaya, L., and 22 others.
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<strong>Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation.</strong>
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Nature 528: 370-375, 2015. Note: Erratum: Nature 532: 402 only, 2016.
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[PubMed: 26649818]
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Wertz, I. E., O'Rourke, K. M., Zhou, H., Eby, M., Aravind, L., Seshagiri, S., Wu, P., Wiesmann, C., Baker, R., Boone, D. L., Ma, A., Koonin, E. V., Dixit, V. M.
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<strong>De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappa-B signalling.</strong>
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Wolfrum, S., Teupser, D., Tan, M., Chen, K. Y., Breslow, J. L.
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<strong>The protective effect of A20 on atherosclerosis in apolipoprotein E-deficient mice is associated with reduced expression of NF-kappa-B target genes.</strong>
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Zhou, Q., Wang, H., Schwartz, D. M., Stoffels, M., Park, Y. H., Zhang, Y., Yang, D., Demirkaya, E., Takeuchi, M., Tsai, W. L., Lyons, J. J., Yu, X., and 29 others.
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<strong>Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.</strong>
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Nature Genet. 48: 67-73, 2016.
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[PubMed: 26642243]
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