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Entry
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- *314370 - UBIQUITIN-LIKE MODIFIER-ACTIVATING ENZYME 1; UBA1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*314370</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<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="#geneStructure">Gene Structure</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="#mapping">Mapping</a>
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<a href="#evolution">Evolution</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/314370">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000130985;t=ENST00000335972" 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=7317" 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=314370" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000130985;t=ENST00000335972" 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_003334,NM_153280,XM_005272649,XM_011543954,XM_017029777,XM_017029778,XM_017029780,XM_047442420,XM_047442421,XM_047442422,XM_047442423,XM_047442424,XM_047442425" 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_003334" 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=314370" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=02440&isoform_id=02440_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/UBA1" 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/24485,35830,340072,2982600,10834678,15278386,23510338,23510340,24418865,119579694,119579695,119579696,119579697,193783543,194375520,194384538,332368019,530421541,768033354,1034675091,1034675093,1034675098,2217394005,2217394008,2217394010,2217394013,2217394015,2217394018,2462630746,2462630748,2462630750,2462630752,2462630754,2462630756,2462630758,2462630760,2462630762,2462630764" 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/P22314" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=7317" 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=ENSG00000130985;t=ENST00000335972" 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=UBA1" 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=UBA1" 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+7317" 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/UBA1" 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:7317" 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/7317" 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=chrX&hgg_gene=ENST00000335972.11&hgg_start=47190847&hgg_end=47215128&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://medlineplus.gov/genetics/gene/uba1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=314370[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=314370[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000130985" 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.gwascentral.org/search?q=UBA1" 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=UBA1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/UBA1" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=UBA1&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/PA37119" 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:12469" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0023143.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:98890" 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/UBA1#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:98890" 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/7317/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=7317" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00006699;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040426-2009" 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">
|
|
<div style="display: table-row">
|
|
<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:7317" 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=UBA1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 719836007<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
314370
|
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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>
|
|
<h3>
|
|
<span class="mim-font">
|
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UBIQUITIN-LIKE MODIFIER-ACTIVATING ENZYME 1; UBA1
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</span>
|
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</h3>
|
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
UBIQUITIN-ACTIVATING ENZYME 1; UBE1<br />
|
|
BN75 TEMPERATURE SENSITIVITY COMPLEMENTING; GXP1
|
|
</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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<a id="includedTitles" class="mim-anchor"></a>
|
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<div>
|
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<p>
|
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
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</span>
|
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</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
TEMPERATURE-SENSITIVE MUTATION, MOUSE, COMPLEMENTATION OF, INCLUDED
|
|
</span>
|
|
</div>
|
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<div>
|
|
<span class="h4 mim-font">
|
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|
|
tsA1S9, INCLUDED<br />
|
|
A1S9T, INCLUDED<br />
|
|
A1S9, INCLUDED
|
|
</span>
|
|
</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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=UBA1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">UBA1</a></em></strong>
|
|
</span>
|
|
</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/X/211?start=-3&limit=10&highlight=211">Xp11.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:47190847-47215128&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'})">X:47,190,847-47,215,128</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
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|
|
</span>
|
|
</p>
|
|
</div>
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=301830,301054" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/211?start=-3&limit=10&highlight=211">
|
|
Xp11.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Spinal muscular atrophy, X-linked 2, infantile
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/301830"> 301830 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
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<p>The UBE1 (UBA1) gene encodes a ubiquitin activating enzyme (E1) that initiates the activation and conjugation of ubiquitin (UBB; <a href="/entry/191339">191339</a>)-like proteins. Modification of proteins with ubiquitin or ubiquitin-like proteins controls many signaling networks and requires a ubiquitin activating enzyme (E1), a ubiquitin conjugating enzyme (E2), and a ubiquitin protein ligase (E3) (<a href="#7" class="mim-tip-reference" title="Jin, J., Li, X., Gygi, S. P., Harper, J. W. <strong>Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging.</strong> Nature 447: 1135-1138, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17597759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17597759</a>] [<a href="https://doi.org/10.1038/nature05902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17597759">Jin et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17597759" 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="#25" class="mim-tip-reference" title="Zacksenhaus, E., Sheinin, R. <strong>Molecular cloning of human A1S9 locus: an X-linked gene essential for progression through S phase of the cell cycle.</strong> Somat. Cell Molec. Genet. 15: 545-553, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2595454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2595454</a>] [<a href="https://doi.org/10.1007/BF01534915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2595454">Zacksenhaus and Sheinin (1989)</a> cloned the human A1S9 cDNA following DNA-mediated gene transfer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2595454" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Zacksenhaus, E., Sheinin, R. <strong>Molecular cloning, primary structure and expression of the human X linked A1S9 gene cDNA which complements the ts A1S9 mouse L cell defect in DNA.</strong> EMBO J. 9: 2923-2929, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2390975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2390975</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1990.tb07483.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2390975">Zacksenhaus and Sheinin (1990)</a> isolated a human A1S9 cDNA from a cDNA library. The predicted 803-amino acid protein was found to be conserved in vertebrates and contains 2 potential nuclear localization signals and no DNA binding domains. Northern blot analysis demonstrated lower expression in quiescent cells but higher and constant expression throughout the cell cycle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2390975" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Handley, P. M., Mueckler, M., Siegel, N. R., Ciechanover, A., Schwartz, A. L. <strong>Molecular cloning, sequence, and tissue distribution of the human ubiquitin-activating enzyme E1.</strong> Proc. Nat. Acad. Sci. 88: 258-262, 1991. Note: Erratum: Proc. Nat. Acad. Sci. 88: 7456 only, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1986373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1986373</a>] [<a href="https://doi.org/10.1073/pnas.88.1.258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1986373">Handley et al. (1991)</a> described the cloning and sequencing of the cDNA for human E1, their term for the ubiquitin-activating enzyme catalyzing the first step in ubiquitin conjugation. The cDNA recognized a single 3.5-kb E1 message that was ubiquitous among tissues and cell lines studied. In vitro translation of the mRNA yielded a major product of approximately 118 kD, which was immunoprecipitated by the antihuman E1 antibody used to identify the clone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1986373" 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="#7" class="mim-tip-reference" title="Jin, J., Li, X., Gygi, S. P., Harper, J. W. <strong>Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging.</strong> Nature 447: 1135-1138, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17597759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17597759</a>] [<a href="https://doi.org/10.1038/nature05902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17597759">Jin et al. (2007)</a> stated that the 1,058-amino acid UBE1 protein contains an N-terminal adenylation domain with 2 ThiF-1 regions, a catalytic cysteine domain, and a C-terminal ubiquitin-fold domain that functions to recruit E2s. Database analysis detected variable UBE1 expression in all human tissues and cell lines examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17597759" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The UBE1 gene contains 27 exons, including an alternative first exon designated 1a (<a href="#17" class="mim-tip-reference" title="Ramser, J., Ahearn, M. E., Lenski, C., Yariz, K. O., Hellebrand, H., von Rhein, M., Clark, R. D., Schmutzler, R. K., Lichtner, P., Hoffman, E. P., Meindl, A., Baumbach-Reardon, L. <strong>Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy.</strong> Am. J. Hum. Genet. 82: 188-193, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18179898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18179898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18179898[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2007.09.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18179898">Ramser et al., 2008</a>). Translation begins in exon 2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18179898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#7" class="mim-tip-reference" title="Jin, J., Li, X., Gygi, S. P., Harper, J. W. <strong>Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging.</strong> Nature 447: 1135-1138, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17597759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17597759</a>] [<a href="https://doi.org/10.1038/nature05902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17597759">Jin et al. (2007)</a> showed that UBE1 was able to transfer ubiquitin to a wide range of E2 substrates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17597759" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Ohtsubo, M., Nishimoto, T. <strong>The gene coding a ubiquitin-activating enzyme may locate on X chromosome.</strong> Biochem. Biophys. Res. Commun. 153: 1173-1178, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3390177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3390177</a>] [<a href="https://doi.org/10.1016/s0006-291x(88)81351-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3390177">Ohtsubo and Nishimoto (1988)</a> studied 2 cell lines with a temperature-sensitive (ts) defect in the S-phase of cell cycle. Two lines failed to complement each other and therefore are presumed to have the same defect as demonstrated in 1 of them: a ts defect in the ubiquitin-activating enzyme. X-linkage was shown for one of the cell lines by demonstration of cosegregation with HPRT in interspecies somatic cell hybrids. The complicated nature of the genetic control of cell growth reflected in ts mutants is indicated by the fact that 23 complementation groups have been identified by cell fusion analysis using polyethylene glycol (<a href="#13" class="mim-tip-reference" title="Nishimoto, T., Basilico, C. <strong>Analysis of a method for selecting temperature-sensitive mutants of BHK cells.</strong> Somat. Cell Genet. 4: 323-340, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/694723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">694723</a>] [<a href="https://doi.org/10.1007/BF01542846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="694723">Nishimoto and Basilico, 1978</a>; <a href="#14" class="mim-tip-reference" title="Nishimoto, T., Sekiguchi, T., Kai, R., Yamashita, K., Takahashi, T., Sekiguchi, M. <strong>Large-scale selection and analysis of temperature-sensitive mutants for cell reproduction from BHK cells.</strong> Somat. Cell Genet. 8: 811-812, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6891837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6891837</a>] [<a href="https://doi.org/10.1007/BF01543021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6891837">Nishimoto et al., 1982</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=694723+6891837+3390177" 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>It turned out that the UBE1 locus is the same as that of the temperature-sensitive gene called A1S9T. <a href="#21" class="mim-tip-reference" title="Willard, H. F., Powers, V. E., Munroe, D. L. G., Brown, C. J. <strong>Identification of a gene on the short arm of the X chromosome that complements a mouse temperature-sensitive defect in DNA synthesis. (Abstract)</strong> Cytogenet. Cell Genet. 46: 716 only, 1987."None>Willard et al. (1987)</a> studied the human gene that complements an X-linked mouse temperature-sensitive defect in DNA synthesis; it is apparently different from the X-linked factor represented by entry <a href="/entry/313650">313650</a> inasmuch as it was found to be located on the short arm rather than on the long arm. The mouse mutant tsA1S9 was characterized as a defect in DNA synthesis affecting conversion of low molecular weight, newly synthesized DNA to mature chromosomal DNA. In hybrid cells between normal human cells and mutant mouse cells, it was found that the X chromosome and specifically the short arm of the X chromosome complemented the defect. <a href="#2" class="mim-tip-reference" title="Brown, C. J., Powers, V. E., Willard, H. F. <strong>Localization of the A1S9T gene to the proximal short arm of the X chromosome. (Abstract)</strong> Cytogenet. Cell Genet. 51: 970 only, 1989."None>Brown et al. (1989)</a> and <a href="#3" class="mim-tip-reference" title="Brown, C. J., Willard, H. F. <strong>Noninactivation of a selectable human X-linked gene that complements a murine temperature-sensitive cell cycle defect.</strong> Am. J. Hum. Genet. 45: 592-598, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2491017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2491017</a>]" pmid="2491017">Brown and Willard (1989)</a> found that a somatic hybrid cell containing the region Xp21.1-p11.1 as its only X-chromosomal material was able to survive at the nonpermissive temperature and thus must contain the A1S9T gene. Since they had previously found that this gene can be expressed from an inactive X chromosome (although not from the Y), the new findings indicated that a second region of the human X chromosome, in addition to the distal Xp22.3 location of other genes that escape inactivation (MIC2, STS, XG), is also not subject to X chromosome inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2491017" 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="Zacksenhaus, E., Sheinin, R. <strong>Identification of human gene complementing ts A1S9 mouse L-cell defect in DNA replication following DNA-mediated gene transfer.</strong> Somat. Cell Molec. Genet. 14: 371-379, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3399963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3399963</a>] [<a href="https://doi.org/10.1007/BF01534645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3399963">Zacksenhaus and Sheinin (1988)</a> isolated a human gene complementing the defect in a temperature-sensitive mouse L-cell line called ts A1S9. The defect is in a gene required for nuclear DNA replication early in the S phase of the cell cycle. DNA-mediated gene transfer (DMGT) was used and the highly repetitive Alu family, which is present in at least 1 copy in virtually every human gene, was used as a marker for the presence of the human DNA in transfected mouse cells. <a href="#24" class="mim-tip-reference" title="Zacksenhaus, E., Sheinin, R. <strong>Identification of human gene complementing ts A1S9 mouse L-cell defect in DNA replication following DNA-mediated gene transfer.</strong> Somat. Cell Molec. Genet. 14: 371-379, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3399963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3399963</a>] [<a href="https://doi.org/10.1007/BF01534645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3399963">Zacksenhaus and Sheinin (1988)</a> stated that this was the first demonstration of transfer of a human S-phase gene. That the gene is X-linked was suggested by the fact that both active and inactive human X chromosomes corrected the defect. The authors quoted observations indicating that the tsA1S9 gene product is not required for polydeoxyribonucleotide chain synthesis per se; thus, the gene does not encode DNA polymerase alpha or DNA ligase. DNA polymerase beta and gamma, as well as poly(ADP-ribose) polymerase, had also been ruled out. Some evidence suggested that the temperature-labile A1S9 protein may participate in DNA topoisomerase-2 activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3399963" 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>Cytokine and protooncogene mRNAs are rapidly degraded through AU-rich elements in the 3-prime untranslated region. Rapid decay involves AU-rich binding protein AUF1 (<a href="/entry/601324">601324</a>), which complexes with heat-shock proteins HSC70 (<a href="/entry/600816">600816</a>) and HSP70 (see <a href="/entry/140550">140550</a>), translation initiation factor EIF4G (<a href="/entry/600495">600495</a>), and poly(A)-binding protein (<a href="/entry/604679">604679</a>). AU-rich mRNA decay is associated with displacement of EIF4G from AUF1, ubiquitination of AUF1, and degradation of AUF1 by proteasomes. Induction of HSP70 by heat shock, downregulation of the ubiquitin-proteasome network, or inactivation of ubiquitinating enzyme E1, all result in HSP70 sequestration of AUF1 in the perinucleus-nucleus, and all 3 processes block decay of AU-rich mRNAs and AUF1 protein. These results link the rapid degradation of cytokine mRNAs to the ubiquitin-proteasome pathway (<a href="#9" class="mim-tip-reference" title="Laroia, G., Cuesta, R., Brewer, G., Schneider, R. J. <strong>Control of mRNA decay by heat shock-ubiquitin-proteasome pathway.</strong> Science 284: 499-502, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10205060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10205060</a>] [<a href="https://doi.org/10.1126/science.284.5413.499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10205060">Laroia et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10205060" 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>Using Southern blot and in situ hybridization, Zacksenhaus et al. (<a href="#22" class="mim-tip-reference" title="Zacksenhaus, E., Sheinin, R., Wang, H. S. <strong>The human S phase gene A1S9 is located at Xp11.23-11.4. (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A169 only, 1989."None>1989</a>, <a href="#23" class="mim-tip-reference" title="Zacksenhaus, E., Sheinin, R., Wang, H. S. <strong>Localization of the human A1S9 gene complementing the ts A1S9 mouse L-cell defect in DNA replication and cell cycle progression to Xp11.2-p11.4.</strong> Cytogenet. Cell Genet. 53: 20-22, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2323223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2323223</a>] [<a href="https://doi.org/10.1159/000132887" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2323223">1990</a>) mapped the A1S9 gene to Xp11.4-p11.2. On the basis of a study of somatic cell hybrids with various deleted human X chromosomes, <a href="#4" class="mim-tip-reference" title="Brown, C. J., Willard, H. F. <strong>Localization of a gene that escapes inactivation to the X chromosome proximal short arm: implications for X inactivation.</strong> Am. J. Hum. Genet. 46: 273-279, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2301397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2301397</a>]" pmid="2301397">Brown and Willard (1990)</a> gave Xp11.3-p11.1 as the location of the A1S9T gene. Combining these data with those of Zacksenhaus et al. (<a href="#22" class="mim-tip-reference" title="Zacksenhaus, E., Sheinin, R., Wang, H. S. <strong>The human S phase gene A1S9 is located at Xp11.23-11.4. (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A169 only, 1989."None>1989</a>, <a href="#23" class="mim-tip-reference" title="Zacksenhaus, E., Sheinin, R., Wang, H. S. <strong>Localization of the human A1S9 gene complementing the ts A1S9 mouse L-cell defect in DNA replication and cell cycle progression to Xp11.2-p11.4.</strong> Cytogenet. Cell Genet. 53: 20-22, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2323223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2323223</a>] [<a href="https://doi.org/10.1159/000132887" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2323223">1990</a>), one might conclude that the location is Xp11.3-p11.2. By high-resolution fluorescence in situ hybridization, Takahashi et al. (<a href="#19" class="mim-tip-reference" title="Takahashi, E.-I., Yamauchi, M., Ayusawa, D., Kaneda, S., Seno, T., Meuth, M., Hori, T.-A. <strong>Chromosome mappings of the human cytidine-5-prime-triphosphate synthetase (CTPS) gene and the human ubiquitin-activating enzyme UBE1 gene by fluorescence in situ hybridization. (Abstract)</strong> Cytogenet. Cell Genet. 58: 1864 only, 1991."None>1991</a>, <a href="#18" class="mim-tip-reference" title="Takahashi, E., Ayusawa, D., Kaneda, S., Itoh, Y., Seno, T., Hori, T. <strong>The human ubiquitin-activating enzyme E1 gene (UBE1) mapped to band Xp11.3-p11.23 by fluorescence in situ hybridization.</strong> Cytogenet. Cell Genet. 59: 268-269, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1544321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1544321</a>] [<a href="https://doi.org/10.1159/000133266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1544321">1992</a>) mapped the UBE1 gene to Xp11.3-p11.23. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1544321+2301397+2323223" 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="#12" class="mim-tip-reference" title="Mitchell, M. J., Woods, D. R., Tucker, P. K., Opp, J. S., Bishop, C. E. <strong>Homology of a candidate spermatogenic gene from the mouse Y chromosome to the ubiquitin-activating enzyme E1.</strong> Nature 354: 483-486, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1684224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1684224</a>] [<a href="https://doi.org/10.1038/354483a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1684224">Mitchell et al. (1991)</a> and <a href="#8" class="mim-tip-reference" title="Kay, G. F., Ashworth, A., Penny, G. D., Dunlop, M., Swift, S., Brockdorff, N., Rastan, S. <strong>A candidate spermatogenesis gene on the mouse Y chromosome is homologous to ubiquitin-activation enzyme E1.</strong> Nature 354: 486-489, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1749428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1749428</a>] [<a href="https://doi.org/10.1038/354486a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1749428">Kay et al. (1991)</a> demonstrated homology of a candidate spermatogenesis gene on the mouse Y chromosome to the UBE1 gene on the X chromosome. <a href="#12" class="mim-tip-reference" title="Mitchell, M. J., Woods, D. R., Tucker, P. K., Opp, J. S., Bishop, C. E. <strong>Homology of a candidate spermatogenic gene from the mouse Y chromosome to the ubiquitin-activating enzyme E1.</strong> Nature 354: 483-486, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1684224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1684224</a>] [<a href="https://doi.org/10.1038/354483a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1684224">Mitchell et al. (1991)</a> reported the isolation of a new testis-specific gene, Sby, mapping to the DNA deleted from the Sxr (sex-reversed) region in the mouse. It showed extensive homology to UBE1. Because of its critical role in nuclear DNA replication, together with the testis-specific expression, it was considered a candidate for the spermatogenic gene Spy, which was known to be required for the survival and proliferation of A spermatogonia during spermatogenesis. <a href="#8" class="mim-tip-reference" title="Kay, G. F., Ashworth, A., Penny, G. D., Dunlop, M., Swift, S., Brockdorff, N., Rastan, S. <strong>A candidate spermatogenesis gene on the mouse Y chromosome is homologous to ubiquitin-activation enzyme E1.</strong> Nature 354: 486-489, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1749428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1749428</a>] [<a href="https://doi.org/10.1038/354486a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1749428">Kay et al. (1991)</a> isolated part of the mouse A1s9 gene, mapped it to the proximal portion of the X chromosome, and showed that it undergoes normal X-inactivation. They also detected 2 copies of the gene on the short arm of the mouse Y chromosome, A1s9Y1 and A1s9Y2. They found that A1s9Y1 is expressed in testis and is lost in the deletion form of Sxr. A1s9X is similar to the Zfx gene (<a href="/entry/314980">314980</a>), which undergoes X-inactivation, yet has homologous sequences on the short arm of the Y chromosome that are expressed in the testis. These Y-linked genes may form part of a coregulated group of genes which function during spermatogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1684224+1749428" 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>Mammalian sex chromosomes are thought to be descended from a homologous pair of autosomes: a testis-determining allele which defined the Y chromosome arose, recombination between the nascent X and Y chromosomes became restricted, and the Y chromosome gradually lost its nonessential genetic functions. This model was originally inferred from the occurrence of a few Y-linked genetic traits, pairing of the X and Y chromosomes during male meiosis, and the existence of X-Y homologous genes. UBE1 is an X-linked gene with a distinct Y-linked homolog in many eutherian (placental) and metatherian (marsupial) mammals. Nonetheless, no UBE1 homolog is detectable on the human Y chromosome. <a href="#11" class="mim-tip-reference" title="Mitchell, M. J., Wilcox, S. A., Watson, J. M., Lerner, J. L., Woods, D. R., Scheffler, J., Hearn, J. P., Bishop, C. E., Marshall Graves, J. A. <strong>The origin and loss of the ubiquitin activating enzyme gene on the mammalian Y chromosome.</strong> Hum. Molec. Genet. 7: 429-434, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9467000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9467000</a>] [<a href="https://doi.org/10.1093/hmg/7.3.429" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9467000">Mitchell et al. (1998)</a> studied extensively the UBE1 homologs in primates and a prototherian mammal, the platypus. Their findings indicated that UBE1 lies within the X-Y pairing segment of the platypus but is absent from the human Y chromosome, having been lost from the Y chromosome during evolution of the primate lineage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9467000" 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>Spinal Muscular Atrophy 2, X-Linked</em></strong></p><p>
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Patients with X-linked spinal muscular atrophy-2 (SMAX2; <a href="/entry/301830">301830</a>) present with hypotonia, areflexia, and multiple congenital contractures associated with loss of anterior horn cells and infantile death. To identify the disease gene, <a href="#17" class="mim-tip-reference" title="Ramser, J., Ahearn, M. E., Lenski, C., Yariz, K. O., Hellebrand, H., von Rhein, M., Clark, R. D., Schmutzler, R. K., Lichtner, P., Hoffman, E. P., Meindl, A., Baumbach-Reardon, L. <strong>Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy.</strong> Am. J. Hum. Genet. 82: 188-193, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18179898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18179898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18179898[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2007.09.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18179898">Ramser et al. (2008)</a> performed large-scale mutation analysis in genes located between markers DXS8080 and DXS7132, the critical interval on Xp11.3-q11.1 indicated by linkage studies. This resulted in detection of 3 rare novel variants in exon 15 of UBE1 (UBA1) that segregated with the disease: 2 missense mutations present in each of 1 XLSMA family (<a href="#0001">314370.0001</a>, <a href="#0002">314370.0002</a>), and 1 synonymous C-to-T substitution (<a href="#0003">314370.0003</a>) identified in another 3 unrelated families. In a sixth family, neither of the 2 missense mutations or the synonymous substitution was identified. <a href="#17" class="mim-tip-reference" title="Ramser, J., Ahearn, M. E., Lenski, C., Yariz, K. O., Hellebrand, H., von Rhein, M., Clark, R. D., Schmutzler, R. K., Lichtner, P., Hoffman, E. P., Meindl, A., Baumbach-Reardon, L. <strong>Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy.</strong> Am. J. Hum. Genet. 82: 188-193, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18179898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18179898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18179898[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2007.09.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18179898">Ramser et al. (2008)</a> demonstrated that the synonymous C-to-T substitution leads to significant reduction of UBA1 expression and alters the methylation pattern of exon 15, implying a plausible role of this DNA element in developmental UBA1 expression in humans. Thus, SMAX2 is one of several neurodegenerative disorders associated with defects in the ubiquitin-proteasome pathway. The authors concluded that their experience indicated that synonymous C-to-T transitions have the potential to affect gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18179898" 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>VEXAS Syndrome</em></strong></p><p>
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Using a genotype-driven approach, <a href="#1" class="mim-tip-reference" title="Beck, D. B., Ferrada, M. A., Sikora, K. A., Ombrello, A. K., Collins, J. C., Pei, W., Balanda, N., Ross, D. L., Cardona, D. O., Wu, Z., Patel, B., Manthiram, K., and 49 others. <strong>Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease.</strong> New Eng. J. Med. 383: 2628-2638, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33108101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33108101</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33108101[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/10.1056/NEJMoa2026834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33108101">Beck et al. (2020)</a> identified an adult-onset inflammatory disorder that exclusively affects males and is associated with de novo somatic mutations in the UBA1 gene. The authors reported 25 unrelated men, all above 45 years of age, with UBA1 mutations who were diagnosed with VEXAS syndrome (VEXAS; <a href="/entry/301054">301054</a>), an acronym for 'vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic.' The patients were ascertained from several large cohorts of over 2,500 patients with undiagnosed or unclassified inflammatory or systemic disorders who underwent genetic investigation. Each patient had 1 of 3 mutations affecting codon Met41 (M41V, <a href="/entry/310370#0004">310370.0004</a>; M41T, <a href="/entry/310370#0005">310370.0005</a>; and M41L, <a href="/entry/310370#0006">310370.0006</a>), which is the translation initiation site for the cytoplasmic UBA1b isoform. The mutations, which were found by exome or targeted sequencing and confirmed by Sanger sequencing, were absent from public databases, including gnomAD. None of the patients had a family history of a similar disorder. All affected men were somatic mosaic for the UBA1 mutation, which was present in peripheral myeloid cells, granulocytes, and monocytes, but not in fibroblasts or mature lymphoid cells. In contrast, bone marrow examination showed that the UBA1 mutations were present in hematopoietic stem cells and in multipotent early marrow progenitor cells. However, patients also had decreased peripheral lymphocyte counts, suggesting that mutant lymphocytes either did not proliferate or did not survive. UBA1 is normally expressed as 2 isoforms differing at the translation site: nuclear UBA1a (initiation at Met1) and cytoplasmic UBA1b (initiation at Met41). In vitro expression of the Met41 mutations into HEK293T cells resulted in loss of UBA1b and the presence of a shorter abnormal isoform, designated UBA1c, that was initiated from a downstream Met67 codon. UBA1c localized to the cytoplasm, but was catalytically impaired compared to UBA1a and UBA1b. The findings suggested that the mutations identified in patients with VEXAS syndrome favored the production of functionally defective cytoplasmic UBA1 isoform. Mutant monocytes derived from the patients showed loss of ubiquitylation, which caused upregulation of the stress and unfolded protein responses, as well as dysregulation of autophagy. These findings suggested that the inflammation observed was mainly due to mutant myeloid cells, although there was also evidence of disrupted B and T cell and neutrophil activation. Transcriptome analysis of patient peripheral blood cells showed a gene expression pattern consistent with the activation of multiple innate immune pathways, including TNF (<a href="/entry/191160">191160</a>), IL6 (<a href="/entry/147620">147620</a>), and IFNG (<a href="/entry/147570">147570</a>). <a href="#1" class="mim-tip-reference" title="Beck, D. B., Ferrada, M. A., Sikora, K. A., Ombrello, A. K., Collins, J. C., Pei, W., Balanda, N., Ross, D. L., Cardona, D. O., Wu, Z., Patel, B., Manthiram, K., and 49 others. <strong>Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease.</strong> New Eng. J. Med. 383: 2628-2638, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33108101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33108101</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33108101[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/10.1056/NEJMoa2026834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33108101">Beck et al. (2020)</a> noted that many patients had myelodysplasia in addition to systemic inflammation and rheumatologic manifestations; they concluded that subcellular ubiquitin regulation and activation play an important role during hematopoiesis and regulation of the immune response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33108101" 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="Poulter, J. A., Collins, J. C., Cargo, C., De Tute, R. M., Evans, P., Cardona, D. O., Bowen, D. T., Cunnington, J. R., Baguley, E., Quinn, M., Green, M., McGonagle, D., Beck, D. B., Werner, A., Savic, S. <strong>Novel somatic mutations in UBA1 as a cause of VEXAS syndrome. (Letter)</strong> Blood 137: 3676-3681, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33690815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33690815</a>] [<a href="https://doi.org/10.1182/blood.2020010286" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33690815">Poulter et al. (2021)</a> identified somatic mutations in the UBA1 gene in 10 unrelated men with VEXAS syndrome. The mutations were identified by Sanger sequencing in peripheral blood or bone marrow from the patients. Eight patients had previously reported mutations; 3 had the M41V mutation and 5 had the M41T mutation. One patient had an S56P mutation (<a href="#0007">314370.0007</a>), which did not affect UBA1 cellular localization or result in isoform expression abnormalities in HEK293 cells transfected with the mutant transcript. <a href="#16" class="mim-tip-reference" title="Poulter, J. A., Collins, J. C., Cargo, C., De Tute, R. M., Evans, P., Cardona, D. O., Bowen, D. T., Cunnington, J. R., Baguley, E., Quinn, M., Green, M., McGonagle, D., Beck, D. B., Werner, A., Savic, S. <strong>Novel somatic mutations in UBA1 as a cause of VEXAS syndrome. (Letter)</strong> Blood 137: 3676-3681, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33690815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33690815</a>] [<a href="https://doi.org/10.1182/blood.2020010286" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33690815">Poulter et al. (2021)</a> demonstrated that the S56P mutation resulted in temperature-dependent impairment of UBA1 catalytic activity. Another patient had a splicing mutation (<a href="#0008">314370.0008</a>), which resulted in multiple incorrectly spliced transcripts and a reduction in the correctly spliced transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33690815" 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 68-year-old man with VEXAS syndrome, <a href="#10" class="mim-tip-reference" title="Lytle, A., Bagg, A. <strong>VEXAS: a vivid new syndrome associated with vacuoles in various hematopoietic cells.</strong> Blood 137: 3690 only, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34196684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34196684</a>] [<a href="https://doi.org/10.1182/blood.2021010714" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34196684">Lytle and Bagg (2021)</a> reported a somatic mutation at Met41 of the UBA1 gene that was identified by whole-exome sequencing. The patient had a history of macrocytic anemia, myeloma, pancytopenia, and relapsing polychrondritis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34196684" 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>Among a cohort of undiagnosed patients with inborn errors of immunity from academic hospitals in the Netherlands, <a href="#20" class="mim-tip-reference" title="van der Made, C. I., Potjewijd, J., Hoogstins, A., Willems, H. P. J., Kwakernaak, A. J., de Sevaux, R. G. L., van Daele, P. L. A., Simons, A., Heijstek, M., Beck, D. B., Netea, M. G., van Paassen, P., Elizabeth Hak, A., van der Veken, L. T., van Gijn, M. E., Hoischen, A., van de Veerdonk, F. L., Leavis, H. L., Rutgers, A. <strong>Adult-onset autoinflammation caused by somatic mutations in UBA1: a Dutch case series of patients with VEXAS.</strong> J. Allergy Clin. Immun. 149: 432-439, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34048852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34048852</a>] [<a href="https://doi.org/10.1016/j.jaci.2021.05.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34048852">van der Made et al. (2022)</a> performed systematic reanalysis of exome sequencing data and targeted Sanger sequencing on those without exome data and identified 12 male patients with VEXAS syndrome and somatic mutations at met41 in the UBA1 gene: 7 with M41T, 4 with M41V, and 1 with M41L. The variant allele fraction varied from 17% to 85%. The authors noted that the low level of variant allele fraction (17%) associated with VEXAS syndrome in one of their patients emphasized the importance of specifically evaluating somatic variants during exome analysis to avoid inappropriate elimination of variants if the variant allele fraction is below a certain threshold. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34048852" 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="#5" class="mim-tip-reference" title="Ferrada, M. A., Savic, S., Cardona, D. O., Collins, J. C., Alessi, H., Gutierrez-Rodrigues, F., Kumar, D. B. U., Wilson, L., Goodspeed, W., Topilow, J. S., Paik, J. J., Poulter, J. A., and 20 others. <strong>Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis.</strong> Blood 140: 1496-1506, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35793467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35793467</a>] [<a href="https://doi.org/10.1182/blood.2022016985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35793467">Ferrada et al. (2022)</a> analyzed 83 patients with VEXAS syndrome due to a somatic pathogenic variant at residue Met41 in the UBA1 gene, which is the start codon for the cytoplasmic UBA1b isoform (see M41V, <a href="#0004">314370.0004</a>; M41T, <a href="#0005">314370.0005</a>; and M41L <a href="#0006">314370.0006</a>). All patients were male and Caucasian with a median age at symptom onset of 66 years. Clinical features were characteristic for the disease, but there were some differences associated with the specific variants. Those with M41V were more likely to have an undifferentiated inflammatory syndrome and showed decreased survival compared to those with M41T or M41L. Patients with M41V were less likely to develop ear chondritis, which was associated with overall better survival in the cohort. Patients with M41T had more inflammatory eye disease compared to the others. Decreased survival was also observed in those who were transfusion-dependent. Detailed in vitro studies of the mutations in HEK293 cells and in patient peripheral mononuclear cells demonstrated that all the mutations resulted in decreased levels of UBA1b, with the largest decrease in cells carrying the M41V mutation (about 2-fold lower than M41L or M41T). These findings indicated that M41V supports less translation of UBA1b than the other variants, and showed that VEXAS syndrome severity inversely correlates with residual UBA1b levels. The authors concluded that there is a certain minimal threshold of cellular UBA1b levels required to initiate disease progression, and that the major cause of disease is loss of UBA1b or its activity, rather than gain of UBA1c. This regulation of residual UBA1b translation thus appears to be fundamental to the pathogenesis of VEXAS syndrome and affects disease prognosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35793467" 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="#1" class="mim-tip-reference" title="Beck, D. B., Ferrada, M. A., Sikora, K. A., Ombrello, A. K., Collins, J. C., Pei, W., Balanda, N., Ross, D. L., Cardona, D. O., Wu, Z., Patel, B., Manthiram, K., and 49 others. <strong>Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease.</strong> New Eng. J. Med. 383: 2628-2638, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33108101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33108101</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33108101[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/10.1056/NEJMoa2026834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33108101">Beck et al. (2020)</a> found that zebrafish with loss of uba1 had growth abnormalities and early death compared to controls. The defects were associated with upregulation of the expression of inflammatory genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33108101" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a family with infantile X-linked spinal muscular atrophy (SMAX2; <a href="/entry/301830">301830</a>), <a href="#17" class="mim-tip-reference" title="Ramser, J., Ahearn, M. E., Lenski, C., Yariz, K. O., Hellebrand, H., von Rhein, M., Clark, R. D., Schmutzler, R. K., Lichtner, P., Hoffman, E. P., Meindl, A., Baumbach-Reardon, L. <strong>Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy.</strong> Am. J. Hum. Genet. 82: 188-193, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18179898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18179898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18179898[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2007.09.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18179898">Ramser et al. (2008)</a> detected a G-to-T transversion of nucleotide 1617 in exon 15 of the UBE1 (UBA1) gene that resulted in substitution of ile for met at codon 539 (M539I). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18179898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a family with infantile X-linked spinal muscular atrophy (SMAX2; <a href="/entry/301830">301830</a>), <a href="#17" class="mim-tip-reference" title="Ramser, J., Ahearn, M. E., Lenski, C., Yariz, K. O., Hellebrand, H., von Rhein, M., Clark, R. D., Schmutzler, R. K., Lichtner, P., Hoffman, E. P., Meindl, A., Baumbach-Reardon, L. <strong>Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy.</strong> Am. J. Hum. Genet. 82: 188-193, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18179898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18179898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18179898[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2007.09.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18179898">Ramser et al. (2008)</a> detected a A-to-G transition of nucleotide 1639 in exon 15 of the UBE1 gene that resulted in substitution of gly for ser at codon 547 (S547G). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18179898" 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">rs80356547 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356547;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=rs80356547" 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=rs80356547" 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=RCV000010436 OR RCV002399316" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010436, RCV002399316" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010436...</a>
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<p>In 3 families with infantile X-linked spinal muscular atrophy (SMAX2; <a href="/entry/301830">301830</a>), <a href="#17" class="mim-tip-reference" title="Ramser, J., Ahearn, M. E., Lenski, C., Yariz, K. O., Hellebrand, H., von Rhein, M., Clark, R. D., Schmutzler, R. K., Lichtner, P., Hoffman, E. P., Meindl, A., Baumbach-Reardon, L. <strong>Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy.</strong> Am. J. Hum. Genet. 82: 188-193, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18179898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18179898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18179898[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2007.09.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18179898">Ramser et al. (2008)</a> detected a novel synonymous C-to-T transition at nucleotide 1731 in exon 15 of the UBE1 gene. This substitution led to significant reduction of UBE1 expression and alteration of the methylation pattern of exon 15. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18179898" 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">rs1936307795 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1936307795;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=rs1936307795" 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=rs1936307795" 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=RCV001038219 OR RCV001261200 OR RCV001265106 OR RCV002255173 OR RCV002363560 OR RCV003411963" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001038219, RCV001261200, RCV001265106, RCV002255173, RCV002363560, RCV003411963" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001038219...</a>
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<p>In 5 unrelated men with VEXAS syndrome (VEXAS; <a href="/entry/301054">301054</a>), <a href="#1" class="mim-tip-reference" title="Beck, D. B., Ferrada, M. A., Sikora, K. A., Ombrello, A. K., Collins, J. C., Pei, W., Balanda, N., Ross, D. L., Cardona, D. O., Wu, Z., Patel, B., Manthiram, K., and 49 others. <strong>Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease.</strong> New Eng. J. Med. 383: 2628-2638, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33108101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33108101</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33108101[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/10.1056/NEJMoa2026834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33108101">Beck et al. (2020)</a> identified a somatic c.121A-G transition (c.121A-G, NM_003334.3) in the UBA1 gene, resulting in a met41-to-val (M41V) substitution at the translation initiation site for the cytoplasmic UBA1b isoform. The mutation, which was found by exome or targeted sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Expression of the variant into HEK293T cells resulted in loss of UBA1b and the presence of a shortened isoform, designated UBA1c, that was initiated from a Met67 codon. UBA1c localized to the cytoplasm. In vitro functional expression studies showed that the UBA1c isoform was catalytically impaired compared to UBA1a and UBA1b, consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33108101" 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 Sanger sequencing of the UBA1 gene in 3 unrelated men with VEXAS, <a href="#16" class="mim-tip-reference" title="Poulter, J. A., Collins, J. C., Cargo, C., De Tute, R. M., Evans, P., Cardona, D. O., Bowen, D. T., Cunnington, J. R., Baguley, E., Quinn, M., Green, M., McGonagle, D., Beck, D. B., Werner, A., Savic, S. <strong>Novel somatic mutations in UBA1 as a cause of VEXAS syndrome. (Letter)</strong> Blood 137: 3676-3681, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33690815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33690815</a>] [<a href="https://doi.org/10.1182/blood.2020010286" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33690815">Poulter et al. (2021)</a> identified a somatic M41V substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33690815" 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 4 of 12 patients with VEXAS syndrome, <a href="#20" class="mim-tip-reference" title="van der Made, C. I., Potjewijd, J., Hoogstins, A., Willems, H. P. J., Kwakernaak, A. J., de Sevaux, R. G. L., van Daele, P. L. A., Simons, A., Heijstek, M., Beck, D. B., Netea, M. G., van Paassen, P., Elizabeth Hak, A., van der Veken, L. T., van Gijn, M. E., Hoischen, A., van de Veerdonk, F. L., Leavis, H. L., Rutgers, A. <strong>Adult-onset autoinflammation caused by somatic mutations in UBA1: a Dutch case series of patients with VEXAS.</strong> J. Allergy Clin. Immun. 149: 432-439, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34048852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34048852</a>] [<a href="https://doi.org/10.1016/j.jaci.2021.05.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34048852">van der Made et al. (2022)</a> identified a somatic M41V mutation in the UBA1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34048852" 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>Variant Function</em></strong></p><p>
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Through detailed in vitro studies of the M41V mutation in HEK293 cells and in VEXAS patient peripheral mononuclear cells, <a href="#5" class="mim-tip-reference" title="Ferrada, M. A., Savic, S., Cardona, D. O., Collins, J. C., Alessi, H., Gutierrez-Rodrigues, F., Kumar, D. B. U., Wilson, L., Goodspeed, W., Topilow, J. S., Paik, J. J., Poulter, J. A., and 20 others. <strong>Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis.</strong> Blood 140: 1496-1506, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35793467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35793467</a>] [<a href="https://doi.org/10.1182/blood.2022016985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35793467">Ferrada et al. (2022)</a> demonstrated that it resulted in decreased levels of UBA1b, about 2-fold lower than M41L or M41T. These findings indicated that M41V does not support translation of UBA1b as well as the other variants, and showed that VEXAS syndrome severity inversely correlates with residual UBA1b levels. The authors concluded that there is a certain minimal threshold of cellular UBA1b levels required to initiate disease progression, and that the major cause of disease is loss of UBA1b or its activity, rather than gain of UBA1c. This regulation of residual UBA1b translation thus appears to be fundamental to the pathogenesis of VEXAS syndrome and affects disease prognosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35793467" 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">rs782416867 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs782416867;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=rs782416867" 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=rs782416867" 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=RCV001239702 OR RCV001261202 OR RCV001265107 OR RCV001702587 OR RCV003405435 OR RCV005040080" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001239702, RCV001261202, RCV001265107, RCV001702587, RCV003405435, RCV005040080" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001239702...</a>
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<p>In 15 unrelated men with VEXAS syndrome (VEXAS; <a href="/entry/301054">301054</a>), <a href="#1" class="mim-tip-reference" title="Beck, D. B., Ferrada, M. A., Sikora, K. A., Ombrello, A. K., Collins, J. C., Pei, W., Balanda, N., Ross, D. L., Cardona, D. O., Wu, Z., Patel, B., Manthiram, K., and 49 others. <strong>Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease.</strong> New Eng. J. Med. 383: 2628-2638, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33108101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33108101</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33108101[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/10.1056/NEJMoa2026834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33108101">Beck et al. (2020)</a> identified a somatic c.122T-C transition (c.122T-C, NM_003334.3) in the UBA1 gene, resulting in a met41-to-thr (M41T) substitution at the translation initiation site for the cytoplasmic UBA1b isoform. The mutation, which was found by exome or targeted sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Expression of the variant into HEK293T cells resulted in loss of UBA1b and the presence of a shortened isoform, designated UBA1c, that was initiated from a Met67 codon. UBA1c localized to the cytoplasm. In vitro functional expression studies showed that the UBA1c isoform was catalytically impaired compared to UBA1a and UBA1b, consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33108101" 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 Sanger sequencing of the UBA1 gene in 5 unrelated men with VEXAS, Poulter et al. (2021) identified a somatic M41T substitution.</p><p>In 7 of 12 patients with VEXAS syndrome, <a href="#20" class="mim-tip-reference" title="van der Made, C. I., Potjewijd, J., Hoogstins, A., Willems, H. P. J., Kwakernaak, A. J., de Sevaux, R. G. L., van Daele, P. L. A., Simons, A., Heijstek, M., Beck, D. B., Netea, M. G., van Paassen, P., Elizabeth Hak, A., van der Veken, L. T., van Gijn, M. E., Hoischen, A., van de Veerdonk, F. L., Leavis, H. L., Rutgers, A. <strong>Adult-onset autoinflammation caused by somatic mutations in UBA1: a Dutch case series of patients with VEXAS.</strong> J. Allergy Clin. Immun. 149: 432-439, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34048852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34048852</a>] [<a href="https://doi.org/10.1016/j.jaci.2021.05.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34048852">van der Made et al. (2022)</a> identified a somatic M41T mutation in the UBA1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34048852" 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>Variant Function</em></strong></p><p>
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Through detailed in vitro studies of the M41T mutation in HEK293 cells and in VEXAS patient peripheral mononuclear cells, <a href="#5" class="mim-tip-reference" title="Ferrada, M. A., Savic, S., Cardona, D. O., Collins, J. C., Alessi, H., Gutierrez-Rodrigues, F., Kumar, D. B. U., Wilson, L., Goodspeed, W., Topilow, J. S., Paik, J. J., Poulter, J. A., and 20 others. <strong>Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis.</strong> Blood 140: 1496-1506, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35793467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35793467</a>] [<a href="https://doi.org/10.1182/blood.2022016985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35793467">Ferrada et al. (2022)</a> demonstrated that it resulted in decreased levels of UBA1b, indicating impaired translation of the isoform. The authors concluded that there is a certain minimal threshold of cellular UBA1b levels required to initiate disease progression, and that the major cause of disease is loss of UBA1b or its activity, rather than gain of UBA1c. This regulation of residual UBA1b translation thus appears to be fundamental to the pathogenesis of VEXAS syndrome and may affect disease prognosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35793467" 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=RCV001261201 OR RCV001265108 OR RCV001366437 OR RCV001815527" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001261201, RCV001265108, RCV001366437, RCV001815527" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001261201...</a>
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<p>In 5 unrelated men with VEXAS syndrome (VEXAS; <a href="/entry/301054">301054</a>), <a href="#1" class="mim-tip-reference" title="Beck, D. B., Ferrada, M. A., Sikora, K. A., Ombrello, A. K., Collins, J. C., Pei, W., Balanda, N., Ross, D. L., Cardona, D. O., Wu, Z., Patel, B., Manthiram, K., and 49 others. <strong>Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease.</strong> New Eng. J. Med. 383: 2628-2638, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33108101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33108101</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33108101[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/10.1056/NEJMoa2026834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33108101">Beck et al. (2020)</a> identified a somatic heterozygous c.121A-C transversion (c.121A-C, NM_003334.3) in the UBA1 gene, resulting in a met41-to-leu (M41L) substitution at the translation initiation site for the cytoplasmic UBA1b isoform. The mutation, which was found by exome or targeted sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Expression of the variant into HEK293T cells resulted in loss of UBA1b and the presence of a shortened isoform, designated UBA1c, that was initiated from a Met67 codon. UBA1c localized to the cytoplasm. In vitro functional expression studies showed that the UBA1c isoform was catalytically impaired compared to UBA1a and UBA1b, consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33108101" 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 1 of 12 patients with VEXAS syndrome, <a href="#20" class="mim-tip-reference" title="van der Made, C. I., Potjewijd, J., Hoogstins, A., Willems, H. P. J., Kwakernaak, A. J., de Sevaux, R. G. L., van Daele, P. L. A., Simons, A., Heijstek, M., Beck, D. B., Netea, M. G., van Paassen, P., Elizabeth Hak, A., van der Veken, L. T., van Gijn, M. E., Hoischen, A., van de Veerdonk, F. L., Leavis, H. L., Rutgers, A. <strong>Adult-onset autoinflammation caused by somatic mutations in UBA1: a Dutch case series of patients with VEXAS.</strong> J. Allergy Clin. Immun. 149: 432-439, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34048852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34048852</a>] [<a href="https://doi.org/10.1016/j.jaci.2021.05.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34048852">van der Made et al. (2022)</a> identified a somatic M41L mutation in the UBA1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34048852" 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>Variant Function</em></strong></p><p>
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Through detailed in vitro studies of the M41L mutation in HEK293 cells and in VEXAS patient peripheral mononuclear cells, <a href="#5" class="mim-tip-reference" title="Ferrada, M. A., Savic, S., Cardona, D. O., Collins, J. C., Alessi, H., Gutierrez-Rodrigues, F., Kumar, D. B. U., Wilson, L., Goodspeed, W., Topilow, J. S., Paik, J. J., Poulter, J. A., and 20 others. <strong>Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis.</strong> Blood 140: 1496-1506, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35793467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35793467</a>] [<a href="https://doi.org/10.1182/blood.2022016985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35793467">Ferrada et al. (2022)</a> demonstrated that it resulted in decreased levels of UBA1b, indicating impaired translation of the isoform. The authors concluded that there is a certain minimal threshold of cellular UBA1b levels required to initiate disease progression, and that the major cause of disease is loss of UBA1b or its activity, rather than gain of UBA1c. This regulation of residual UBA1b translation thus appears to be fundamental to the pathogenesis of VEXAS syndrome and may affect disease prognosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35793467" 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">rs2147250370 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2147250370;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=rs2147250370" 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=rs2147250370" 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=RCV001726682 OR RCV002539756" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001726682, RCV002539756" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001726682...</a>
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<p>In a man (patient 9) with VEXAS syndrome (VEXAS; <a href="/entry/301054">301054</a>), <a href="#16" class="mim-tip-reference" title="Poulter, J. A., Collins, J. C., Cargo, C., De Tute, R. M., Evans, P., Cardona, D. O., Bowen, D. T., Cunnington, J. R., Baguley, E., Quinn, M., Green, M., McGonagle, D., Beck, D. B., Werner, A., Savic, S. <strong>Novel somatic mutations in UBA1 as a cause of VEXAS syndrome. (Letter)</strong> Blood 137: 3676-3681, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33690815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33690815</a>] [<a href="https://doi.org/10.1182/blood.2020010286" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33690815">Poulter et al. (2021)</a> identified a somatic c.167C-T transition (c.167C-T, NM_153280) in the UBA1 gene, resulting in a ser56-to-phe (S56P) substitution. The mutation was identified by Sanger sequencing of the UBA1 gene and was not present in the gnomAD database. Testing in patient blood cells showed that myeloid cells predominantly had the mutant S56P allele, whereas B- and T-cell lineage populations predominantly were wildtype. The mutation did not affect UBA1 cellular localization or result in isoform expression abnormalities in HEK293 cells transfected with the mutant transcript. <a href="#16" class="mim-tip-reference" title="Poulter, J. A., Collins, J. C., Cargo, C., De Tute, R. M., Evans, P., Cardona, D. O., Bowen, D. T., Cunnington, J. R., Baguley, E., Quinn, M., Green, M., McGonagle, D., Beck, D. B., Werner, A., Savic, S. <strong>Novel somatic mutations in UBA1 as a cause of VEXAS syndrome. (Letter)</strong> Blood 137: 3676-3681, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33690815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33690815</a>] [<a href="https://doi.org/10.1182/blood.2020010286" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33690815">Poulter et al. (2021)</a> demonstrated that the mutation resulted in temperature-dependent impairment of UBA1 catalytic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33690815" 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">rs2147250287 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2147250287;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=rs2147250287" 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=rs2147250287" 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=RCV001726683 OR RCV003771873" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001726683, RCV003771873" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001726683...</a>
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<p>In a man (patient 10) with VEXAS syndrome (VEXAS; <a href="/entry/301054">301054</a>), <a href="#16" class="mim-tip-reference" title="Poulter, J. A., Collins, J. C., Cargo, C., De Tute, R. M., Evans, P., Cardona, D. O., Bowen, D. T., Cunnington, J. R., Baguley, E., Quinn, M., Green, M., McGonagle, D., Beck, D. B., Werner, A., Savic, S. <strong>Novel somatic mutations in UBA1 as a cause of VEXAS syndrome. (Letter)</strong> Blood 137: 3676-3681, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33690815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33690815</a>] [<a href="https://doi.org/10.1182/blood.2020010286" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33690815">Poulter et al. (2021)</a> identified a somatic c.118-1G-C transversion (c.118-1G-C, NM_153280) at the acceptor splice site of exon 3 of the UBA1 gene, predicted to result in a splicing abnormality. The mutation was identified by Sanger sequencing of the UBA1 gene and was not present in the gnomAD database. Analysis of patient RNA demonstrated multiple incorrectly spliced transcripts and a reduction in the correctly spliced transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33690815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="Beck2020" class="mim-anchor"></a>
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Beck, D. B., Ferrada, M. A., Sikora, K. A., Ombrello, A. K., Collins, J. C., Pei, W., Balanda, N., Ross, D. L., Cardona, D. O., Wu, Z., Patel, B., Manthiram, K., and 49 others.
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<strong>Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease.</strong>
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New Eng. J. Med. 383: 2628-2638, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33108101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33108101</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33108101[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=33108101" 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/10.1056/NEJMoa2026834" target="_blank">Full Text</a>]
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Brown, C. J., Powers, V. E., Willard, H. F.
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<strong>Localization of the A1S9T gene to the proximal short arm of the X chromosome. (Abstract)</strong>
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Cytogenet. Cell Genet. 51: 970 only, 1989.
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<strong>Noninactivation of a selectable human X-linked gene that complements a murine temperature-sensitive cell cycle defect.</strong>
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Am. J. Hum. Genet. 45: 592-598, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2491017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2491017</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2491017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Localization of a gene that escapes inactivation to the X chromosome proximal short arm: implications for X inactivation.</strong>
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Am. J. Hum. Genet. 46: 273-279, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2301397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2301397</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2301397" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Ferrada, M. A., Savic, S., Cardona, D. O., Collins, J. C., Alessi, H., Gutierrez-Rodrigues, F., Kumar, D. B. U., Wilson, L., Goodspeed, W., Topilow, J. S., Paik, J. J., Poulter, J. A., and 20 others.
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<strong>Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis.</strong>
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Blood 140: 1496-1506, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35793467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35793467</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35793467" 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/10.1182/blood.2022016985" target="_blank">Full Text</a>]
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Handley, P. M., Mueckler, M., Siegel, N. R., Ciechanover, A., Schwartz, A. L.
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<strong>Molecular cloning, sequence, and tissue distribution of the human ubiquitin-activating enzyme E1.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3399963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3399963</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3399963" 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/BF01534645" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="Zacksenhaus1989" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zacksenhaus, E., Sheinin, R.
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<strong>Molecular cloning of human A1S9 locus: an X-linked gene essential for progression through S phase of the cell cycle.</strong>
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Somat. Cell Molec. Genet. 15: 545-553, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2595454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2595454</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2595454" 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/BF01534915" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Zacksenhaus1990" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zacksenhaus, E., Sheinin, R.
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<strong>Molecular cloning, primary structure and expression of the human X linked A1S9 gene cDNA which complements the ts A1S9 mouse L cell defect in DNA.</strong>
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EMBO J. 9: 2923-2929, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2390975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2390975</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2390975" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/j.1460-2075.1990.tb07483.x" target="_blank">Full Text</a>]
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</p>
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</ol>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 02/06/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 02/02/2023<br>Sonja A. Rasmussen - updated : 12/20/2022<br>Hilary J. Vernon - updated : 09/30/2021<br>Cassandra L. Kniffin - updated : 11/10/2020<br>Victor A. McKusick - updated : 2/19/2008<br>Patricia A. Hartz - updated : 7/30/2007<br>Ada Hamosh - updated : 4/16/1999<br>Victor A. McKusick - updated : 4/23/1998
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 1/9/1989
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 02/06/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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ckniffin : 02/02/2023<br>carol : 12/21/2022<br>carol : 12/20/2022<br>carol : 10/04/2021<br>carol : 10/04/2021<br>carol : 09/30/2021<br>carol : 02/20/2021<br>alopez : 02/19/2021<br>alopez : 02/19/2021<br>carol : 01/25/2021<br>carol : 11/12/2020<br>ckniffin : 11/10/2020<br>carol : 03/14/2013<br>mgross : 2/6/2012<br>alopez : 6/26/2008<br>alopez : 2/27/2008<br>terry : 2/19/2008<br>carol : 8/20/2007<br>terry : 7/30/2007<br>mgross : 3/14/2000<br>alopez : 4/16/1999<br>carol : 4/23/1998<br>terry : 4/14/1998<br>carol : 3/17/1994<br>mimadm : 2/28/1994<br>carol : 6/17/1993<br>carol : 5/27/1993<br>carol : 4/7/1993<br>supermim : 3/17/1992
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 314370
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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UBIQUITIN-LIKE MODIFIER-ACTIVATING ENZYME 1; UBA1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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UBIQUITIN-ACTIVATING ENZYME 1; UBE1<br />
|
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BN75 TEMPERATURE SENSITIVITY COMPLEMENTING; GXP1
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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TEMPERATURE-SENSITIVE MUTATION, MOUSE, COMPLEMENTATION OF, INCLUDED
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</span>
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</div>
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<div>
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<span class="h4 mim-font">
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tsA1S9, INCLUDED<br />
|
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A1S9T, INCLUDED<br />
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A1S9, INCLUDED
|
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: UBA1</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 719836007;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: Xp11.3
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Genomic coordinates <span class="small">(GRCh38)</span> : X:47,190,847-47,215,128 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
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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="2">
|
|
<span class="mim-font">
|
|
Xp11.3
|
|
</span>
|
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</td>
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Spinal muscular atrophy, X-linked 2, infantile
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
301830
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
X-linked recessive
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
VEXAS syndrome, somatic
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
301054
|
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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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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
|
|
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>The UBE1 (UBA1) gene encodes a ubiquitin activating enzyme (E1) that initiates the activation and conjugation of ubiquitin (UBB; 191339)-like proteins. Modification of proteins with ubiquitin or ubiquitin-like proteins controls many signaling networks and requires a ubiquitin activating enzyme (E1), a ubiquitin conjugating enzyme (E2), and a ubiquitin protein ligase (E3) (Jin et al., 2007). </p>
|
|
</span>
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<div>
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<br />
|
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</div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
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</div>
|
|
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|
|
<span class="mim-text-font">
|
|
<p>Zacksenhaus and Sheinin (1989) cloned the human A1S9 cDNA following DNA-mediated gene transfer. </p><p>Zacksenhaus and Sheinin (1990) isolated a human A1S9 cDNA from a cDNA library. The predicted 803-amino acid protein was found to be conserved in vertebrates and contains 2 potential nuclear localization signals and no DNA binding domains. Northern blot analysis demonstrated lower expression in quiescent cells but higher and constant expression throughout the cell cycle. </p><p>Handley et al. (1991) described the cloning and sequencing of the cDNA for human E1, their term for the ubiquitin-activating enzyme catalyzing the first step in ubiquitin conjugation. The cDNA recognized a single 3.5-kb E1 message that was ubiquitous among tissues and cell lines studied. In vitro translation of the mRNA yielded a major product of approximately 118 kD, which was immunoprecipitated by the antihuman E1 antibody used to identify the clone. </p><p>Jin et al. (2007) stated that the 1,058-amino acid UBE1 protein contains an N-terminal adenylation domain with 2 ThiF-1 regions, a catalytic cysteine domain, and a C-terminal ubiquitin-fold domain that functions to recruit E2s. Database analysis detected variable UBE1 expression in all human tissues and cell lines examined. </p>
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|
</span>
|
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<div>
|
|
<br />
|
|
</div>
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|
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|
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>The UBE1 gene contains 27 exons, including an alternative first exon designated 1a (Ramser et al., 2008). Translation begins in exon 2. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
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|
|
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<span class="mim-text-font">
|
|
<p>Jin et al. (2007) showed that UBE1 was able to transfer ubiquitin to a wide range of E2 substrates. </p><p>Ohtsubo and Nishimoto (1988) studied 2 cell lines with a temperature-sensitive (ts) defect in the S-phase of cell cycle. Two lines failed to complement each other and therefore are presumed to have the same defect as demonstrated in 1 of them: a ts defect in the ubiquitin-activating enzyme. X-linkage was shown for one of the cell lines by demonstration of cosegregation with HPRT in interspecies somatic cell hybrids. The complicated nature of the genetic control of cell growth reflected in ts mutants is indicated by the fact that 23 complementation groups have been identified by cell fusion analysis using polyethylene glycol (Nishimoto and Basilico, 1978; Nishimoto et al., 1982). </p><p>It turned out that the UBE1 locus is the same as that of the temperature-sensitive gene called A1S9T. Willard et al. (1987) studied the human gene that complements an X-linked mouse temperature-sensitive defect in DNA synthesis; it is apparently different from the X-linked factor represented by entry 313650 inasmuch as it was found to be located on the short arm rather than on the long arm. The mouse mutant tsA1S9 was characterized as a defect in DNA synthesis affecting conversion of low molecular weight, newly synthesized DNA to mature chromosomal DNA. In hybrid cells between normal human cells and mutant mouse cells, it was found that the X chromosome and specifically the short arm of the X chromosome complemented the defect. Brown et al. (1989) and Brown and Willard (1989) found that a somatic hybrid cell containing the region Xp21.1-p11.1 as its only X-chromosomal material was able to survive at the nonpermissive temperature and thus must contain the A1S9T gene. Since they had previously found that this gene can be expressed from an inactive X chromosome (although not from the Y), the new findings indicated that a second region of the human X chromosome, in addition to the distal Xp22.3 location of other genes that escape inactivation (MIC2, STS, XG), is also not subject to X chromosome inactivation. </p><p>Zacksenhaus and Sheinin (1988) isolated a human gene complementing the defect in a temperature-sensitive mouse L-cell line called ts A1S9. The defect is in a gene required for nuclear DNA replication early in the S phase of the cell cycle. DNA-mediated gene transfer (DMGT) was used and the highly repetitive Alu family, which is present in at least 1 copy in virtually every human gene, was used as a marker for the presence of the human DNA in transfected mouse cells. Zacksenhaus and Sheinin (1988) stated that this was the first demonstration of transfer of a human S-phase gene. That the gene is X-linked was suggested by the fact that both active and inactive human X chromosomes corrected the defect. The authors quoted observations indicating that the tsA1S9 gene product is not required for polydeoxyribonucleotide chain synthesis per se; thus, the gene does not encode DNA polymerase alpha or DNA ligase. DNA polymerase beta and gamma, as well as poly(ADP-ribose) polymerase, had also been ruled out. Some evidence suggested that the temperature-labile A1S9 protein may participate in DNA topoisomerase-2 activity. </p><p>Cytokine and protooncogene mRNAs are rapidly degraded through AU-rich elements in the 3-prime untranslated region. Rapid decay involves AU-rich binding protein AUF1 (601324), which complexes with heat-shock proteins HSC70 (600816) and HSP70 (see 140550), translation initiation factor EIF4G (600495), and poly(A)-binding protein (604679). AU-rich mRNA decay is associated with displacement of EIF4G from AUF1, ubiquitination of AUF1, and degradation of AUF1 by proteasomes. Induction of HSP70 by heat shock, downregulation of the ubiquitin-proteasome network, or inactivation of ubiquitinating enzyme E1, all result in HSP70 sequestration of AUF1 in the perinucleus-nucleus, and all 3 processes block decay of AU-rich mRNAs and AUF1 protein. These results link the rapid degradation of cytokine mRNAs to the ubiquitin-proteasome pathway (Laroia et al., 1999). </p>
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</span>
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<div>
|
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<br />
|
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</div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
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</h4>
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<span class="mim-text-font">
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<p>Using Southern blot and in situ hybridization, Zacksenhaus et al. (1989, 1990) mapped the A1S9 gene to Xp11.4-p11.2. On the basis of a study of somatic cell hybrids with various deleted human X chromosomes, Brown and Willard (1990) gave Xp11.3-p11.1 as the location of the A1S9T gene. Combining these data with those of Zacksenhaus et al. (1989, 1990), one might conclude that the location is Xp11.3-p11.2. By high-resolution fluorescence in situ hybridization, Takahashi et al. (1991, 1992) mapped the UBE1 gene to Xp11.3-p11.23. </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Evolution</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>Mitchell et al. (1991) and Kay et al. (1991) demonstrated homology of a candidate spermatogenesis gene on the mouse Y chromosome to the UBE1 gene on the X chromosome. Mitchell et al. (1991) reported the isolation of a new testis-specific gene, Sby, mapping to the DNA deleted from the Sxr (sex-reversed) region in the mouse. It showed extensive homology to UBE1. Because of its critical role in nuclear DNA replication, together with the testis-specific expression, it was considered a candidate for the spermatogenic gene Spy, which was known to be required for the survival and proliferation of A spermatogonia during spermatogenesis. Kay et al. (1991) isolated part of the mouse A1s9 gene, mapped it to the proximal portion of the X chromosome, and showed that it undergoes normal X-inactivation. They also detected 2 copies of the gene on the short arm of the mouse Y chromosome, A1s9Y1 and A1s9Y2. They found that A1s9Y1 is expressed in testis and is lost in the deletion form of Sxr. A1s9X is similar to the Zfx gene (314980), which undergoes X-inactivation, yet has homologous sequences on the short arm of the Y chromosome that are expressed in the testis. These Y-linked genes may form part of a coregulated group of genes which function during spermatogenesis. </p><p>Mammalian sex chromosomes are thought to be descended from a homologous pair of autosomes: a testis-determining allele which defined the Y chromosome arose, recombination between the nascent X and Y chromosomes became restricted, and the Y chromosome gradually lost its nonessential genetic functions. This model was originally inferred from the occurrence of a few Y-linked genetic traits, pairing of the X and Y chromosomes during male meiosis, and the existence of X-Y homologous genes. UBE1 is an X-linked gene with a distinct Y-linked homolog in many eutherian (placental) and metatherian (marsupial) mammals. Nonetheless, no UBE1 homolog is detectable on the human Y chromosome. Mitchell et al. (1998) studied extensively the UBE1 homologs in primates and a prototherian mammal, the platypus. Their findings indicated that UBE1 lies within the X-Y pairing segment of the platypus but is absent from the human Y chromosome, having been lost from the Y chromosome during evolution of the primate lineage. </p>
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</span>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Spinal Muscular Atrophy 2, X-Linked</em></strong></p><p>
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Patients with X-linked spinal muscular atrophy-2 (SMAX2; 301830) present with hypotonia, areflexia, and multiple congenital contractures associated with loss of anterior horn cells and infantile death. To identify the disease gene, Ramser et al. (2008) performed large-scale mutation analysis in genes located between markers DXS8080 and DXS7132, the critical interval on Xp11.3-q11.1 indicated by linkage studies. This resulted in detection of 3 rare novel variants in exon 15 of UBE1 (UBA1) that segregated with the disease: 2 missense mutations present in each of 1 XLSMA family (314370.0001, 314370.0002), and 1 synonymous C-to-T substitution (314370.0003) identified in another 3 unrelated families. In a sixth family, neither of the 2 missense mutations or the synonymous substitution was identified. Ramser et al. (2008) demonstrated that the synonymous C-to-T substitution leads to significant reduction of UBA1 expression and alters the methylation pattern of exon 15, implying a plausible role of this DNA element in developmental UBA1 expression in humans. Thus, SMAX2 is one of several neurodegenerative disorders associated with defects in the ubiquitin-proteasome pathway. The authors concluded that their experience indicated that synonymous C-to-T transitions have the potential to affect gene expression. </p><p><strong><em>VEXAS Syndrome</em></strong></p><p>
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Using a genotype-driven approach, Beck et al. (2020) identified an adult-onset inflammatory disorder that exclusively affects males and is associated with de novo somatic mutations in the UBA1 gene. The authors reported 25 unrelated men, all above 45 years of age, with UBA1 mutations who were diagnosed with VEXAS syndrome (VEXAS; 301054), an acronym for 'vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic.' The patients were ascertained from several large cohorts of over 2,500 patients with undiagnosed or unclassified inflammatory or systemic disorders who underwent genetic investigation. Each patient had 1 of 3 mutations affecting codon Met41 (M41V, 310370.0004; M41T, 310370.0005; and M41L, 310370.0006), which is the translation initiation site for the cytoplasmic UBA1b isoform. The mutations, which were found by exome or targeted sequencing and confirmed by Sanger sequencing, were absent from public databases, including gnomAD. None of the patients had a family history of a similar disorder. All affected men were somatic mosaic for the UBA1 mutation, which was present in peripheral myeloid cells, granulocytes, and monocytes, but not in fibroblasts or mature lymphoid cells. In contrast, bone marrow examination showed that the UBA1 mutations were present in hematopoietic stem cells and in multipotent early marrow progenitor cells. However, patients also had decreased peripheral lymphocyte counts, suggesting that mutant lymphocytes either did not proliferate or did not survive. UBA1 is normally expressed as 2 isoforms differing at the translation site: nuclear UBA1a (initiation at Met1) and cytoplasmic UBA1b (initiation at Met41). In vitro expression of the Met41 mutations into HEK293T cells resulted in loss of UBA1b and the presence of a shorter abnormal isoform, designated UBA1c, that was initiated from a downstream Met67 codon. UBA1c localized to the cytoplasm, but was catalytically impaired compared to UBA1a and UBA1b. The findings suggested that the mutations identified in patients with VEXAS syndrome favored the production of functionally defective cytoplasmic UBA1 isoform. Mutant monocytes derived from the patients showed loss of ubiquitylation, which caused upregulation of the stress and unfolded protein responses, as well as dysregulation of autophagy. These findings suggested that the inflammation observed was mainly due to mutant myeloid cells, although there was also evidence of disrupted B and T cell and neutrophil activation. Transcriptome analysis of patient peripheral blood cells showed a gene expression pattern consistent with the activation of multiple innate immune pathways, including TNF (191160), IL6 (147620), and IFNG (147570). Beck et al. (2020) noted that many patients had myelodysplasia in addition to systemic inflammation and rheumatologic manifestations; they concluded that subcellular ubiquitin regulation and activation play an important role during hematopoiesis and regulation of the immune response. </p><p>Poulter et al. (2021) identified somatic mutations in the UBA1 gene in 10 unrelated men with VEXAS syndrome. The mutations were identified by Sanger sequencing in peripheral blood or bone marrow from the patients. Eight patients had previously reported mutations; 3 had the M41V mutation and 5 had the M41T mutation. One patient had an S56P mutation (314370.0007), which did not affect UBA1 cellular localization or result in isoform expression abnormalities in HEK293 cells transfected with the mutant transcript. Poulter et al. (2021) demonstrated that the S56P mutation resulted in temperature-dependent impairment of UBA1 catalytic activity. Another patient had a splicing mutation (314370.0008), which resulted in multiple incorrectly spliced transcripts and a reduction in the correctly spliced transcript. </p><p>In a 68-year-old man with VEXAS syndrome, Lytle and Bagg (2021) reported a somatic mutation at Met41 of the UBA1 gene that was identified by whole-exome sequencing. The patient had a history of macrocytic anemia, myeloma, pancytopenia, and relapsing polychrondritis. </p><p>Among a cohort of undiagnosed patients with inborn errors of immunity from academic hospitals in the Netherlands, van der Made et al. (2022) performed systematic reanalysis of exome sequencing data and targeted Sanger sequencing on those without exome data and identified 12 male patients with VEXAS syndrome and somatic mutations at met41 in the UBA1 gene: 7 with M41T, 4 with M41V, and 1 with M41L. The variant allele fraction varied from 17% to 85%. The authors noted that the low level of variant allele fraction (17%) associated with VEXAS syndrome in one of their patients emphasized the importance of specifically evaluating somatic variants during exome analysis to avoid inappropriate elimination of variants if the variant allele fraction is below a certain threshold. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</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>Ferrada et al. (2022) analyzed 83 patients with VEXAS syndrome due to a somatic pathogenic variant at residue Met41 in the UBA1 gene, which is the start codon for the cytoplasmic UBA1b isoform (see M41V, 314370.0004; M41T, 314370.0005; and M41L 314370.0006). All patients were male and Caucasian with a median age at symptom onset of 66 years. Clinical features were characteristic for the disease, but there were some differences associated with the specific variants. Those with M41V were more likely to have an undifferentiated inflammatory syndrome and showed decreased survival compared to those with M41T or M41L. Patients with M41V were less likely to develop ear chondritis, which was associated with overall better survival in the cohort. Patients with M41T had more inflammatory eye disease compared to the others. Decreased survival was also observed in those who were transfusion-dependent. Detailed in vitro studies of the mutations in HEK293 cells and in patient peripheral mononuclear cells demonstrated that all the mutations resulted in decreased levels of UBA1b, with the largest decrease in cells carrying the M41V mutation (about 2-fold lower than M41L or M41T). These findings indicated that M41V supports less translation of UBA1b than the other variants, and showed that VEXAS syndrome severity inversely correlates with residual UBA1b levels. The authors concluded that there is a certain minimal threshold of cellular UBA1b levels required to initiate disease progression, and that the major cause of disease is loss of UBA1b or its activity, rather than gain of UBA1c. This regulation of residual UBA1b translation thus appears to be fundamental to the pathogenesis of VEXAS syndrome and affects disease prognosis. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Beck et al. (2020) found that zebrafish with loss of uba1 had growth abnormalities and early death compared to controls. The defects were associated with upregulation of the expression of inflammatory genes. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>8 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 SPINAL MUSCULAR ATROPHY, X-LINKED 2</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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UBA1, MET539ILE
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<br />
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SNP: rs80356545,
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ClinVar: RCV000010434
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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 family with infantile X-linked spinal muscular atrophy (SMAX2; 301830), Ramser et al. (2008) detected a G-to-T transversion of nucleotide 1617 in exon 15 of the UBE1 (UBA1) gene that resulted in substitution of ile for met at codon 539 (M539I). </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 SPINAL MUSCULAR ATROPHY, X-LINKED 2</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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UBA1, SER547GLY
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<br />
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SNP: rs80356546,
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ClinVar: RCV000010435
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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 family with infantile X-linked spinal muscular atrophy (SMAX2; 301830), Ramser et al. (2008) detected a A-to-G transition of nucleotide 1639 in exon 15 of the UBE1 gene that resulted in substitution of gly for ser at codon 547 (S547G). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 SPINAL MUSCULAR ATROPHY, X-LINKED 2</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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UBA1, ASN577ASN
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<br />
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|
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SNP: rs80356547,
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ClinVar: RCV000010436, RCV002399316
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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 3 families with infantile X-linked spinal muscular atrophy (SMAX2; 301830), Ramser et al. (2008) detected a novel synonymous C-to-T transition at nucleotide 1731 in exon 15 of the UBE1 gene. This substitution led to significant reduction of UBE1 expression and alteration of the methylation pattern of exon 15. </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>.0004 VEXAS SYNDROME, SOMATIC</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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UBA1, MET41VAL
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<br />
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SNP: rs1936307795,
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ClinVar: RCV001038219, RCV001261200, RCV001265106, RCV002255173, RCV002363560, RCV003411963
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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 5 unrelated men with VEXAS syndrome (VEXAS; 301054), Beck et al. (2020) identified a somatic c.121A-G transition (c.121A-G, NM_003334.3) in the UBA1 gene, resulting in a met41-to-val (M41V) substitution at the translation initiation site for the cytoplasmic UBA1b isoform. The mutation, which was found by exome or targeted sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Expression of the variant into HEK293T cells resulted in loss of UBA1b and the presence of a shortened isoform, designated UBA1c, that was initiated from a Met67 codon. UBA1c localized to the cytoplasm. In vitro functional expression studies showed that the UBA1c isoform was catalytically impaired compared to UBA1a and UBA1b, consistent with a loss of function. </p><p>By Sanger sequencing of the UBA1 gene in 3 unrelated men with VEXAS, Poulter et al. (2021) identified a somatic M41V substitution. </p><p>In 4 of 12 patients with VEXAS syndrome, van der Made et al. (2022) identified a somatic M41V mutation in the UBA1 gene. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Through detailed in vitro studies of the M41V mutation in HEK293 cells and in VEXAS patient peripheral mononuclear cells, Ferrada et al. (2022) demonstrated that it resulted in decreased levels of UBA1b, about 2-fold lower than M41L or M41T. These findings indicated that M41V does not support translation of UBA1b as well as the other variants, and showed that VEXAS syndrome severity inversely correlates with residual UBA1b levels. The authors concluded that there is a certain minimal threshold of cellular UBA1b levels required to initiate disease progression, and that the major cause of disease is loss of UBA1b or its activity, rather than gain of UBA1c. This regulation of residual UBA1b translation thus appears to be fundamental to the pathogenesis of VEXAS syndrome and affects disease prognosis. </p>
|
|
</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>.0005 VEXAS SYNDROME, SOMATIC</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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UBA1, MET41THR
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<br />
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|
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SNP: rs782416867,
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ClinVar: RCV001239702, RCV001261202, RCV001265107, RCV001702587, RCV003405435, RCV005040080
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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 15 unrelated men with VEXAS syndrome (VEXAS; 301054), Beck et al. (2020) identified a somatic c.122T-C transition (c.122T-C, NM_003334.3) in the UBA1 gene, resulting in a met41-to-thr (M41T) substitution at the translation initiation site for the cytoplasmic UBA1b isoform. The mutation, which was found by exome or targeted sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Expression of the variant into HEK293T cells resulted in loss of UBA1b and the presence of a shortened isoform, designated UBA1c, that was initiated from a Met67 codon. UBA1c localized to the cytoplasm. In vitro functional expression studies showed that the UBA1c isoform was catalytically impaired compared to UBA1a and UBA1b, consistent with a loss of function. </p><p>By Sanger sequencing of the UBA1 gene in 5 unrelated men with VEXAS, Poulter et al. (2021) identified a somatic M41T substitution.</p><p>In 7 of 12 patients with VEXAS syndrome, van der Made et al. (2022) identified a somatic M41T mutation in the UBA1 gene. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Through detailed in vitro studies of the M41T mutation in HEK293 cells and in VEXAS patient peripheral mononuclear cells, Ferrada et al. (2022) demonstrated that it resulted in decreased levels of UBA1b, indicating impaired translation of the isoform. The authors concluded that there is a certain minimal threshold of cellular UBA1b levels required to initiate disease progression, and that the major cause of disease is loss of UBA1b or its activity, rather than gain of UBA1c. This regulation of residual UBA1b translation thus appears to be fundamental to the pathogenesis of VEXAS syndrome and may affect disease prognosis. </p>
|
|
</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 VEXAS SYNDROME, SOMATIC</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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UBA1, MET41LEU
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<br />
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SNP: rs1936307795,
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ClinVar: RCV001261201, RCV001265108, RCV001366437, RCV001815527
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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 5 unrelated men with VEXAS syndrome (VEXAS; 301054), Beck et al. (2020) identified a somatic heterozygous c.121A-C transversion (c.121A-C, NM_003334.3) in the UBA1 gene, resulting in a met41-to-leu (M41L) substitution at the translation initiation site for the cytoplasmic UBA1b isoform. The mutation, which was found by exome or targeted sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Expression of the variant into HEK293T cells resulted in loss of UBA1b and the presence of a shortened isoform, designated UBA1c, that was initiated from a Met67 codon. UBA1c localized to the cytoplasm. In vitro functional expression studies showed that the UBA1c isoform was catalytically impaired compared to UBA1a and UBA1b, consistent with a loss of function. </p><p>In 1 of 12 patients with VEXAS syndrome, van der Made et al. (2022) identified a somatic M41L mutation in the UBA1 gene. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Through detailed in vitro studies of the M41L mutation in HEK293 cells and in VEXAS patient peripheral mononuclear cells, Ferrada et al. (2022) demonstrated that it resulted in decreased levels of UBA1b, indicating impaired translation of the isoform. The authors concluded that there is a certain minimal threshold of cellular UBA1b levels required to initiate disease progression, and that the major cause of disease is loss of UBA1b or its activity, rather than gain of UBA1c. This regulation of residual UBA1b translation thus appears to be fundamental to the pathogenesis of VEXAS syndrome and may affect disease prognosis. </p>
|
|
</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 VEXAS SYNDROME, SOMATIC</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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UBA1, SER56PHE
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<br />
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SNP: rs2147250370,
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ClinVar: RCV001726682, RCV002539756
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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 man (patient 9) with VEXAS syndrome (VEXAS; 301054), Poulter et al. (2021) identified a somatic c.167C-T transition (c.167C-T, NM_153280) in the UBA1 gene, resulting in a ser56-to-phe (S56P) substitution. The mutation was identified by Sanger sequencing of the UBA1 gene and was not present in the gnomAD database. Testing in patient blood cells showed that myeloid cells predominantly had the mutant S56P allele, whereas B- and T-cell lineage populations predominantly were wildtype. The mutation did not affect UBA1 cellular localization or result in isoform expression abnormalities in HEK293 cells transfected with the mutant transcript. Poulter et al. (2021) demonstrated that the mutation resulted in temperature-dependent impairment of UBA1 catalytic activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 VEXAS SYNDROME, SOMATIC</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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UBA1, IVS2AS, G-C, -1
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<br />
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SNP: rs2147250287,
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ClinVar: RCV001726683, RCV003771873
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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 man (patient 10) with VEXAS syndrome (VEXAS; 301054), Poulter et al. (2021) identified a somatic c.118-1G-C transversion (c.118-1G-C, NM_153280) at the acceptor splice site of exon 3 of the UBA1 gene, predicted to result in a splicing abnormality. The mutation was identified by Sanger sequencing of the UBA1 gene and was not present in the gnomAD database. Analysis of patient RNA demonstrated multiple incorrectly spliced transcripts and a reduction in the correctly spliced transcript. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Beck, D. B., Ferrada, M. A., Sikora, K. A., Ombrello, A. K., Collins, J. C., Pei, W., Balanda, N., Ross, D. L., Cardona, D. O., Wu, Z., Patel, B., Manthiram, K., and 49 others.
|
|
<strong>Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease.</strong>
|
|
New Eng. J. Med. 383: 2628-2638, 2020.
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[PubMed: 33108101]
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[Full Text: https://doi.org/10.1056/NEJMoa2026834]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Brown, C. J., Powers, V. E., Willard, H. F.
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<strong>Localization of the A1S9T gene to the proximal short arm of the X chromosome. (Abstract)</strong>
|
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Cytogenet. Cell Genet. 51: 970 only, 1989.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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|
Brown, C. J., Willard, H. F.
|
|
<strong>Noninactivation of a selectable human X-linked gene that complements a murine temperature-sensitive cell cycle defect.</strong>
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Am. J. Hum. Genet. 45: 592-598, 1989.
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[PubMed: 2491017]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Brown, C. J., Willard, H. F.
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<strong>Localization of a gene that escapes inactivation to the X chromosome proximal short arm: implications for X inactivation.</strong>
|
|
Am. J. Hum. Genet. 46: 273-279, 1990.
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[PubMed: 2301397]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Ferrada, M. A., Savic, S., Cardona, D. O., Collins, J. C., Alessi, H., Gutierrez-Rodrigues, F., Kumar, D. B. U., Wilson, L., Goodspeed, W., Topilow, J. S., Paik, J. J., Poulter, J. A., and 20 others.
|
|
<strong>Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis.</strong>
|
|
Blood 140: 1496-1506, 2022.
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|
|
[PubMed: 35793467]
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[Full Text: https://doi.org/10.1182/blood.2022016985]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Handley, P. M., Mueckler, M., Siegel, N. R., Ciechanover, A., Schwartz, A. L.
|
|
<strong>Molecular cloning, sequence, and tissue distribution of the human ubiquitin-activating enzyme E1.</strong>
|
|
Proc. Nat. Acad. Sci. 88: 258-262, 1991. Note: Erratum: Proc. Nat. Acad. Sci. 88: 7456 only, 1991.
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[PubMed: 1986373]
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[Full Text: https://doi.org/10.1073/pnas.88.1.258]
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Jin, J., Li, X., Gygi, S. P., Harper, J. W.
|
|
<strong>Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging.</strong>
|
|
Nature 447: 1135-1138, 2007.
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|
[PubMed: 17597759]
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[Full Text: https://doi.org/10.1038/nature05902]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kay, G. F., Ashworth, A., Penny, G. D., Dunlop, M., Swift, S., Brockdorff, N., Rastan, S.
|
|
<strong>A candidate spermatogenesis gene on the mouse Y chromosome is homologous to ubiquitin-activation enzyme E1.</strong>
|
|
Nature 354: 486-489, 1991.
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|
[PubMed: 1749428]
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|
[Full Text: https://doi.org/10.1038/354486a0]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Laroia, G., Cuesta, R., Brewer, G., Schneider, R. J.
|
|
<strong>Control of mRNA decay by heat shock-ubiquitin-proteasome pathway.</strong>
|
|
Science 284: 499-502, 1999.
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|
[PubMed: 10205060]
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|
|
[Full Text: https://doi.org/10.1126/science.284.5413.499]
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</p>
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</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Lytle, A., Bagg, A.
|
|
<strong>VEXAS: a vivid new syndrome associated with vacuoles in various hematopoietic cells.</strong>
|
|
Blood 137: 3690 only, 2021.
|
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|
|
[PubMed: 34196684]
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|
|
[Full Text: https://doi.org/10.1182/blood.2021010714]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Mitchell, M. J., Wilcox, S. A., Watson, J. M., Lerner, J. L., Woods, D. R., Scheffler, J., Hearn, J. P., Bishop, C. E., Marshall Graves, J. A.
|
|
<strong>The origin and loss of the ubiquitin activating enzyme gene on the mammalian Y chromosome.</strong>
|
|
Hum. Molec. Genet. 7: 429-434, 1998.
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|
|
[PubMed: 9467000]
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|
|
[Full Text: https://doi.org/10.1093/hmg/7.3.429]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Mitchell, M. J., Woods, D. R., Tucker, P. K., Opp, J. S., Bishop, C. E.
|
|
<strong>Homology of a candidate spermatogenic gene from the mouse Y chromosome to the ubiquitin-activating enzyme E1.</strong>
|
|
Nature 354: 483-486, 1991.
|
|
|
|
|
|
[PubMed: 1684224]
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|
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|
|
[Full Text: https://doi.org/10.1038/354483a0]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Nishimoto, T., Basilico, C.
|
|
<strong>Analysis of a method for selecting temperature-sensitive mutants of BHK cells.</strong>
|
|
Somat. Cell Genet. 4: 323-340, 1978.
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[PubMed: 694723]
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|
|
[Full Text: https://doi.org/10.1007/BF01542846]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Nishimoto, T., Sekiguchi, T., Kai, R., Yamashita, K., Takahashi, T., Sekiguchi, M.
|
|
<strong>Large-scale selection and analysis of temperature-sensitive mutants for cell reproduction from BHK cells.</strong>
|
|
Somat. Cell Genet. 8: 811-812, 1982.
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|
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|
|
|
[PubMed: 6891837]
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|
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|
|
[Full Text: https://doi.org/10.1007/BF01543021]
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|
|
</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Ohtsubo, M., Nishimoto, T.
|
|
<strong>The gene coding a ubiquitin-activating enzyme may locate on X chromosome.</strong>
|
|
Biochem. Biophys. Res. Commun. 153: 1173-1178, 1988.
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|
|
[PubMed: 3390177]
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|
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[Full Text: https://doi.org/10.1016/s0006-291x(88)81351-2]
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Poulter, J. A., Collins, J. C., Cargo, C., De Tute, R. M., Evans, P., Cardona, D. O., Bowen, D. T., Cunnington, J. R., Baguley, E., Quinn, M., Green, M., McGonagle, D., Beck, D. B., Werner, A., Savic, S.
|
|
<strong>Novel somatic mutations in UBA1 as a cause of VEXAS syndrome. (Letter)</strong>
|
|
Blood 137: 3676-3681, 2021.
|
|
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|
|
[PubMed: 33690815]
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|
|
[Full Text: https://doi.org/10.1182/blood.2020010286]
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|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Ramser, J., Ahearn, M. E., Lenski, C., Yariz, K. O., Hellebrand, H., von Rhein, M., Clark, R. D., Schmutzler, R. K., Lichtner, P., Hoffman, E. P., Meindl, A., Baumbach-Reardon, L.
|
|
<strong>Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy.</strong>
|
|
Am. J. Hum. Genet. 82: 188-193, 2008.
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|
[PubMed: 18179898]
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[Full Text: https://doi.org/10.1016/j.ajhg.2007.09.009]
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</p>
|
|
</li>
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<li>
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<p class="mim-text-font">
|
|
Takahashi, E., Ayusawa, D., Kaneda, S., Itoh, Y., Seno, T., Hori, T.
|
|
<strong>The human ubiquitin-activating enzyme E1 gene (UBE1) mapped to band Xp11.3-p11.23 by fluorescence in situ hybridization.</strong>
|
|
Cytogenet. Cell Genet. 59: 268-269, 1992.
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|
[PubMed: 1544321]
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[Full Text: https://doi.org/10.1159/000133266]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
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|
Takahashi, E.-I., Yamauchi, M., Ayusawa, D., Kaneda, S., Seno, T., Meuth, M., Hori, T.-A.
|
|
<strong>Chromosome mappings of the human cytidine-5-prime-triphosphate synthetase (CTPS) gene and the human ubiquitin-activating enzyme UBE1 gene by fluorescence in situ hybridization. (Abstract)</strong>
|
|
Cytogenet. Cell Genet. 58: 1864 only, 1991.
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|
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
van der Made, C. I., Potjewijd, J., Hoogstins, A., Willems, H. P. J., Kwakernaak, A. J., de Sevaux, R. G. L., van Daele, P. L. A., Simons, A., Heijstek, M., Beck, D. B., Netea, M. G., van Paassen, P., Elizabeth Hak, A., van der Veken, L. T., van Gijn, M. E., Hoischen, A., van de Veerdonk, F. L., Leavis, H. L., Rutgers, A.
|
|
<strong>Adult-onset autoinflammation caused by somatic mutations in UBA1: a Dutch case series of patients with VEXAS.</strong>
|
|
J. Allergy Clin. Immun. 149: 432-439, 2022.
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|
|
[PubMed: 34048852]
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[Full Text: https://doi.org/10.1016/j.jaci.2021.05.014]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Willard, H. F., Powers, V. E., Munroe, D. L. G., Brown, C. J.
|
|
<strong>Identification of a gene on the short arm of the X chromosome that complements a mouse temperature-sensitive defect in DNA synthesis. (Abstract)</strong>
|
|
Cytogenet. Cell Genet. 46: 716 only, 1987.
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|
|
</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Zacksenhaus, E., Sheinin, R., Wang, H. S.
|
|
<strong>The human S phase gene A1S9 is located at Xp11.23-11.4. (Abstract)</strong>
|
|
Am. J. Hum. Genet. 45 (suppl.): A169 only, 1989.
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|
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Zacksenhaus, E., Sheinin, R., Wang, H. S.
|
|
<strong>Localization of the human A1S9 gene complementing the ts A1S9 mouse L-cell defect in DNA replication and cell cycle progression to Xp11.2-p11.4.</strong>
|
|
Cytogenet. Cell Genet. 53: 20-22, 1990.
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|
|
[PubMed: 2323223]
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[Full Text: https://doi.org/10.1159/000132887]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Zacksenhaus, E., Sheinin, R.
|
|
<strong>Identification of human gene complementing ts A1S9 mouse L-cell defect in DNA replication following DNA-mediated gene transfer.</strong>
|
|
Somat. Cell Molec. Genet. 14: 371-379, 1988.
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|
|
|
[PubMed: 3399963]
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|
|
[Full Text: https://doi.org/10.1007/BF01534645]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Zacksenhaus, E., Sheinin, R.
|
|
<strong>Molecular cloning of human A1S9 locus: an X-linked gene essential for progression through S phase of the cell cycle.</strong>
|
|
Somat. Cell Molec. Genet. 15: 545-553, 1989.
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|
|
[PubMed: 2595454]
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[Full Text: https://doi.org/10.1007/BF01534915]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Zacksenhaus, E., Sheinin, R.
|
|
<strong>Molecular cloning, primary structure and expression of the human X linked A1S9 gene cDNA which complements the ts A1S9 mouse L cell defect in DNA.</strong>
|
|
EMBO J. 9: 2923-2929, 1990.
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|
|
[PubMed: 2390975]
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[Full Text: https://doi.org/10.1002/j.1460-2075.1990.tb07483.x]
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</p>
|
|
</li>
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</ol>
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<div>
|
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<br />
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</div>
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</div>
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</div>
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<div>
|
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<div class="row">
|
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Contributors:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Anne M. Stumpf - updated : 02/06/2023<br>Cassandra L. Kniffin - updated : 02/02/2023<br>Sonja A. Rasmussen - updated : 12/20/2022<br>Hilary J. Vernon - updated : 09/30/2021<br>Cassandra L. Kniffin - updated : 11/10/2020<br>Victor A. McKusick - updated : 2/19/2008<br>Patricia A. Hartz - updated : 7/30/2007<br>Ada Hamosh - updated : 4/16/1999<br>Victor A. McKusick - updated : 4/23/1998
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
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<div>
|
|
<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Victor A. McKusick : 1/9/1989
|
|
</span>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
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alopez : 02/06/2023<br>ckniffin : 02/02/2023<br>carol : 12/21/2022<br>carol : 12/20/2022<br>carol : 10/04/2021<br>carol : 10/04/2021<br>carol : 09/30/2021<br>carol : 02/20/2021<br>alopez : 02/19/2021<br>alopez : 02/19/2021<br>carol : 01/25/2021<br>carol : 11/12/2020<br>ckniffin : 11/10/2020<br>carol : 03/14/2013<br>mgross : 2/6/2012<br>alopez : 6/26/2008<br>alopez : 2/27/2008<br>terry : 2/19/2008<br>carol : 8/20/2007<br>terry : 7/30/2007<br>mgross : 3/14/2000<br>alopez : 4/16/1999<br>carol : 4/23/1998<br>terry : 4/14/1998<br>carol : 3/17/1994<br>mimadm : 2/28/1994<br>carol : 6/17/1993<br>carol : 5/27/1993<br>carol : 4/7/1993<br>supermim : 3/17/1992
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