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Entry
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- *601623 - UBIQUITIN-PROTEIN LIGASE E3A; UBE3A
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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">*601623</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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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</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="#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/601623">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li 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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<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=ENSG00000114062;t=ENST00000648336" 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=7337" 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=601623" 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=ENSG00000114062;t=ENST00000648336" 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_000462,NM_001354505,NM_001354506,NM_001354507,NM_001354508,NM_001354509,NM_001354511,NM_001354512,NM_001354513,NM_001354523,NM_001354526,NM_001354538,NM_001354539,NM_001354540,NM_001354541,NM_001354542,NM_001354543,NM_001354544,NM_001354545,NM_001354546,NM_001354547,NM_001354548,NM_001354549,NM_001354550,NM_001354551,NM_001374461,NM_130838,NM_130839,NR_148916,XM_011521995,XM_017022547,XM_017022548,XM_017022550,XM_024450043,XM_047433007,XM_047433008,XM_047433009,XM_047433010,XM_047433011,XM_047433012,XM_047433013,XM_047433014,XM_047433015,XM_047433016,XM_047433017,XM_047433018,XM_047433019,XM_047433020,XM_047433021" 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_130839" 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=601623" 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=03375&isoform_id=03375_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/UBE3A" 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/178745,1495430,1495432,1495434,1495436,1872514,2361031,2853320,3421128,3421130,3421136,3421142,3421149,3421153,3421159,11385658,14424503,19718762,19718764,19718766,37589039,55416027,55416028,119578046,119578047,119578048,119578049,158256246,158258465,215274240,767985224,1034591761,1034591763,1034591767,1233951509,1233951511,1233951513,1233951515,1233951517,1233951519,1233951521,1233951523,1233951525,1233951527,1233951529,1233951531,1233951533,1245709114,1245709116,1245709118,1245709120,1245709122,1245709124,1245709126,1245709128,1245709130,1245709132,1245715149,1370467190,1753014231,2217302523,2217302527,2217302529,2217302531,2217302534,2217302536,2217302539,2217302541,2217302543,2217302546,2217302548,2217302550,2217302552,2217302554,2217302556,2462545762,2462545764,2462545766,2462545768,2462545770,2462545772,2462545774,2462545776,2462545778,2462545780,2462545782,2462545784,2462545786,2462545788,2462545790,2462545792,2462545794,2462545796,2462545798,2462545800" 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/Q05086" 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=7337" 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=ENSG00000114062;t=ENST00000648336" 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=UBE3A" 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=UBE3A" 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+7337" 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/UBE3A" 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:7337" 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/7337" 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=chr15&hgg_gene=ENST00000648336.2&hgg_start=25333728&hgg_end=25439056&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:12496" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:12496" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/ube3a" 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=601623[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=601623[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/UBE3A/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000114062" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=UBE3A" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=UBE3A" 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=UBE3A" 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://ngrl.man.ac.uk/lovd2/home.php?select_db=UBE3A" 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=UBE3A&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/PA37144" 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:12496" 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/FBgn0061469.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:105098" 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/UBE3A#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:105098" 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/7337/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002614/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=7337" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-041114-190" 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="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:601623" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7337" 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=UBE3A&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> 76880004<br />
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<strong>ICD10CM:</strong> Q93.51<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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601623
|
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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UBIQUITIN-PROTEIN LIGASE E3A; UBE3A
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</span>
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</h3>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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HUMAN PAPILLOMAVIRUS E6-ASSOCIATED PROTEIN; E6AP
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=UBE3A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">UBE3A</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/15/32?start=-3&limit=10&highlight=32">15q11.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:25333728-25439056&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'})">15:25,333,728-25,439,056</a> </span>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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Inheritance
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15q11.2
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Angelman syndrome
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<a href="/entry/105830"> 105830 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/601623" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/601623" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>UBE3A functions as both an E3 ligase in the ubiquitin proteasome pathway and as a transcriptional coactivator. The UBE3A gene is subject to genomic imprinting, with preferential maternal-specific expression in brain and, more specifically, in neurons but not in glia (<a href="#4" class="mim-tip-reference" title="Dindot, S. V., Antalffy, B. A., Bhattacharjee, M. B., Beaudet, A. L. <strong>The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology.</strong> Hum. Molec. Genet. 17: 111-118, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17940072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17940072</a>] [<a href="https://doi.org/10.1093/hmg/ddm288" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17940072">Dindot et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17940072" 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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<br />
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<div>
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<a id="cloning" class="mim-anchor"></a>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>E6AP was initially identified as a cellular protein that mediates in vitro association of the human papillomavirus E6 protein with p53 (<a href="/entry/191170">191170</a>), leading to the ubiquitin-dependent degradation of p53 (<a href="#13" class="mim-tip-reference" title="Huibregtse, J. M., Scheffner, M., Howley, P. M. <strong>A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18.</strong> EMBO J. 10: 4129-4135, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1661671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1661671</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1991.tb04990.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1661671">Huibregtse et al., 1991</a>; <a href="#32" class="mim-tip-reference" title="Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J., Howley, P. M. <strong>The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53.</strong> Cell 63: 1129-1136, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2175676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2175676</a>] [<a href="https://doi.org/10.1016/0092-8674(90)90409-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2175676">Scheffner et al., 1990</a>). <a href="#14" class="mim-tip-reference" title="Huibregtse, J. M., Scheffner, M., Howley, P. M. <strong>Cloning and expression of the cDNA for E6-AP, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53.</strong> Molec. Cell. Biol. 13: 775-784, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8380895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8380895</a>] [<a href="https://doi.org/10.1128/mcb.13.2.775-784.1993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8380895">Huibregtse et al. (1993)</a> cloned the E6AP gene and studied the expressed protein's association with p53 and E6. The 865-amino acid E6AP protein has a native molecular mass of approximately 100 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1661671+8380895+2175676" 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="#39" class="mim-tip-reference" title="Yamamoto, Y., Huibregtse, J. M., Howley, P. M. <strong>The human E6-AP gene (UBE3A) encodes three potential protein isoforms generated by differential splicing.</strong> Genomics 41: 263-266, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9143503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9143503</a>] [<a href="https://doi.org/10.1006/geno.1997.4617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9143503">Yamamoto et al. (1997)</a> noted that UBE3A belongs to a family of functionally related proteins defined by a conserved C-terminal 350-amino acid HECT domain. Using RT-PCR, <a href="#39" class="mim-tip-reference" title="Yamamoto, Y., Huibregtse, J. M., Howley, P. M. <strong>The human E6-AP gene (UBE3A) encodes three potential protein isoforms generated by differential splicing.</strong> Genomics 41: 263-266, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9143503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9143503</a>] [<a href="https://doi.org/10.1006/geno.1997.4617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9143503">Yamamoto et al. (1997)</a> identified several UBE3A mRNAs encoding protein isoforms that differed at their N termini. Each mRNA was expressed in all cell lines tested. <a href="#17" class="mim-tip-reference" title="Kishino, T., Wagstaff, J. <strong>Genomic organization of the UBE3A/E6-AP gene and related pseudogenes.</strong> Genomics 47: 101-107, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9465301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9465301</a>] [<a href="https://doi.org/10.1006/geno.1997.5093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9465301">Kishino and Wagstaff (1998)</a> identified additional alternatively spliced forms of UBE3A mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9143503+9465301" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using VCY2 (BPY2; <a href="/entry/400013">400013</a>) as bait in a yeast 2-hybrid screen of a testis cDNA library, followed by RT-PCR of testis mRNA, <a href="#37" class="mim-tip-reference" title="Wong, E. Y. M., Tse, J. Y. M., Yao, K.-M., Tam, P.-C., Yeung, W. S. B. <strong>VCY2 protein interacts with the HECT domain of ubiquitin-protein ligase E3A.</strong> Biochem. Biophys. Res. Commun. 296: 1104-1111, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12207887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12207887</a>] [<a href="https://doi.org/10.1016/s0006-291x(02)02040-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12207887">Wong et al. (2002)</a> cloned UBE3A. The deduced 873-amino acid protein contains a C-terminal HECT domain. Northern blot analysis detected strong expression of 1.4- and 2-kb UBE3A transcripts and weaker expression of 4- and 5-kb transcripts in testis and prostate. The 1.4- and 2-kb transcripts were also detected in small intestine and colon. RT-PCR detected UBE3A expression in ejaculated human sperm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12207887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using fractionation analysis, <a href="#8" class="mim-tip-reference" title="Furumai, R., Tamada, K., Liu, X., Takumi, T. <strong>UBE3A regulates the transcription of IRF, an antiviral immunity.</strong> Hum. Molec. Genet. 28: 1947-1958, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30690483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30690483</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30690483[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddz019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30690483">Furumai et al. (2019)</a> showed that Ube3a localized mainly to nuclei of mouse neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30690483" 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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<br />
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<div>
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<a id="geneStructure" class="mim-anchor"></a>
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<h4 href="#mimGeneStructureFold" id="mimGeneStructureToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimGeneStructureToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p><a href="#39" class="mim-tip-reference" title="Yamamoto, Y., Huibregtse, J. M., Howley, P. M. <strong>The human E6-AP gene (UBE3A) encodes three potential protein isoforms generated by differential splicing.</strong> Genomics 41: 263-266, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9143503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9143503</a>] [<a href="https://doi.org/10.1006/geno.1997.4617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9143503">Yamamoto et al. (1997)</a> found that the coding region of the UBE3A gene is composed of 10 exons and spans at least 60 kb. The 5-prime UTR is composed of at least 4 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9143503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Kishino, T., Wagstaff, J. <strong>Genomic organization of the UBE3A/E6-AP gene and related pseudogenes.</strong> Genomics 47: 101-107, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9465301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9465301</a>] [<a href="https://doi.org/10.1006/geno.1997.5093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9465301">Kishino and Wagstaff (1998)</a> found that the UBE3A gene has at least 16 exons, including 6 exons that encode the 5-prime UTR. The gene spans approximately 120 kb, with transcription oriented from telomere to centromere. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9465301" 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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<br />
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<div>
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<a id="mapping" class="mim-anchor"></a>
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<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<strong>Mapping</strong>
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<p>UBE3A maps within the critical region for Angelman syndrome (AS; <a href="/entry/105830">105830</a>) on chromosome 15q11-q13 (<a href="#24" class="mim-tip-reference" title="Matsuura, T., Sutcliffe, J. S., Fang, P., Galjaard, R.-J., Jiang, Y., Benton, C. S., Rommens, J. M., Beaudet, A. L. <strong>De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome.</strong> Nature Genet. 15: 74-77, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988172</a>] [<a href="https://doi.org/10.1038/ng0197-74" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988172">Matsuura et al., 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8988172" 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="#33" class="mim-tip-reference" title="Smith, S. E. P., Zhou, Y.-D., Zhang, G., Jin, Z., Stoppel, D. C., Anderson, M. P. <strong>Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice.</strong> Sci. Transl. Med. 3: 103ra97, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21974935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21974935</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21974935[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/scitranslmed.3002627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21974935">Smith et al. (2011)</a> stated that the mouse Ube3a gene maps to a region of chromosome 7 that is syntenic to human chromosome 15. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21974935" 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>Pseudogenes</em></strong></p><p>
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<a href="#17" class="mim-tip-reference" title="Kishino, T., Wagstaff, J. <strong>Genomic organization of the UBE3A/E6-AP gene and related pseudogenes.</strong> Genomics 47: 101-107, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9465301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9465301</a>] [<a href="https://doi.org/10.1006/geno.1997.5093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9465301">Kishino and Wagstaff (1998)</a> mapped 2 processed UBE3A pseudogenes to chromosomes 2 and 21. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9465301" 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="#31" class="mim-tip-reference" title="Scheffner, M., Huibregtse, J. M., Vierstra, R. D., Howley, P. M. <strong>The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53.</strong> Cell 75: 495-505, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8221889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8221889</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90384-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8221889">Scheffner et al. (1993)</a> found that E6AP is an E3 ubiquitin-protein ligase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8221889" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using yeast 2-hybrid and coimmunoprecipitation analyses, <a href="#37" class="mim-tip-reference" title="Wong, E. Y. M., Tse, J. Y. M., Yao, K.-M., Tam, P.-C., Yeung, W. S. B. <strong>VCY2 protein interacts with the HECT domain of ubiquitin-protein ligase E3A.</strong> Biochem. Biophys. Res. Commun. 296: 1104-1111, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12207887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12207887</a>] [<a href="https://doi.org/10.1016/s0006-291x(02)02040-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12207887">Wong et al. (2002)</a> showed that VCY2 interacted with the HECT domain of UBE3A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12207887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Lu, Y., Wang, F., Li, Y., Ferris, J., Lee, J. A., Gao, F.-B. <strong>The Drosophila homologue of the Angelman syndrome ubiquitin ligase regulates the formation of terminal dendritic branches.</strong> Hum. Molec. Genet. 18: 454-462, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18996915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18996915</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18996915[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18996915">Lu et al. (2009)</a> showed that Ube3a was not essential for viability in Drosophila but that loss of Ube3a activity reduced dendritic branching of sensory neurons in the peripheral nervous system and slowed the growth of terminal dendritic fine processes. Ube3a overexpression in Drosophila decreased dendritic branching, suggesting that maintaining a proper level of UBE3A is critical for normal dendritic patterning. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18996915" 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="#9" class="mim-tip-reference" title="Greer, P. L., Hanayama, R., Bloodgood, B. L., Mardinly, A. R., Lipton, D. M., Flavell, S. W., Kim, T.-K., Griffith, E. C., Waldon, Z., Maehr, R., Ploegh, H. L., Chowdhury, S., Worley, P. F., Steen, J., Greenberg, M. E. <strong>The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating Arc.</strong> Cell 140: 704-716, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20211139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20211139</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20211139[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2010.01.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20211139">Greer et al. (2010)</a> found that neuronal activity elevated the expression of rodent Ube3a transcripts in cultured neurons and in mouse brain, concomitant with elevated surface expression of AMPA-type glutamate receptors (AMPARs) (see GLUR1, or GRIA1; <a href="/entry/138248">138248</a>) and increased frequency of miniature excitatory postsynaptic currents. Activity specifically elevated expression of Ube3a transcripts initiating from the highly conserved promoters 1 and 3, which contain binding sites for the activity-related transcription factor Mef2 (MEF2A; <a href="/entry/600660">600660</a>). Overexpression, knockdown, and mutation experiments revealed that Ube3a elevated postsynaptic surface expression of Glur1 by downregulating Arc (<a href="/entry/612461">612461</a>), a mediator of Glur1 endocytosis. Downregulation of Arc by Ube3a required the ubiquitin ligase activity of Ube3a and was blocked by a protease inhibitor. <a href="#9" class="mim-tip-reference" title="Greer, P. L., Hanayama, R., Bloodgood, B. L., Mardinly, A. R., Lipton, D. M., Flavell, S. W., Kim, T.-K., Griffith, E. C., Waldon, Z., Maehr, R., Ploegh, H. L., Chowdhury, S., Worley, P. F., Steen, J., Greenberg, M. E. <strong>The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating Arc.</strong> Cell 140: 704-716, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20211139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20211139</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20211139[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2010.01.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20211139">Greer et al. (2010)</a> concluded that UBE3A elevates the surface expression and activity of AMPARs by directing the proteasomal degradation of ARC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20211139" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Margolis, S. S., Salogiannis, J., Lipton, D. M., Mandel-Brehm, C., Wills, Z. P., Mardinly, A. R., Hu, L., Greer, P. L., Bikoff, J. B., Ho, H.-Y. H., Soskis, M. J., Sahin, M., Greenberg, M. E. <strong>EphB-mediated degradation of the RhoA GEF ephexin5 relieves a developmental brake on excitatory synapse formation.</strong> Cell 143: 442-455, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21029865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21029865</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21029865[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2010.09.038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21029865">Margolis et al. (2010)</a> found that Ube3a had a role in degrading the Rhoa (<a href="/entry/165390">165390</a>) guanine nucleotide exchange factor ephexin-5 (E5, or ARHGEF15; <a href="/entry/608504">608504</a>), which regulates synapse formation in developing mouse neurons. Binding of E5 to ephrin receptor Ephb2 (<a href="/entry/600997">600997</a>) inhibited both the tyrosine kinase activity of Ephb2 and excitatory synapse formation. The E5-Ephb2 interaction was terminated by the binding of ephrin B (see EFNB1; <a href="/entry/300035">300035</a>) to Ephb2, which resulted in tyrosine phosphorylation, release, and destabilization of E5 and permitted the formation of excitatory synapses. Degradation of E5 required its binding to Ube3a and was inhibited by an inactive Ube3a mutant or proteasome inhibition. <a href="#23" class="mim-tip-reference" title="Margolis, S. S., Salogiannis, J., Lipton, D. M., Mandel-Brehm, C., Wills, Z. P., Mardinly, A. R., Hu, L., Greer, P. L., Bikoff, J. B., Ho, H.-Y. H., Soskis, M. J., Sahin, M., Greenberg, M. E. <strong>EphB-mediated degradation of the RhoA GEF ephexin5 relieves a developmental brake on excitatory synapse formation.</strong> Cell 143: 442-455, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21029865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21029865</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21029865[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2010.09.038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21029865">Margolis et al. (2010)</a> found that E5 expression was elevated in a mouse model of Angelman syndrome, suggesting that elevated E5 expression during development may contribute to abnormal cognitive function in Angelman syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21029865" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using yeast 2-hybrid analysis and coprecipitation analysis of cotransfected and endogenous proteins, <a href="#19" class="mim-tip-reference" title="Kuhnle, S., Kogel, U., Glockzin, S., Marquardt, A., Ciechanover, A., Matentzoglu, K., Scheffner, M. <strong>Physical and functional interaction of the HECT ubiquitin-protein ligases E6AP and HERC2.</strong> J. Biol. Chem. 286: 19410-19416, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21493713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21493713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21493713[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M110.205211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21493713">Kuhnle et al. (2011)</a> found that the E3 ubiquitin ligase HERC2 interacted with the 852-amino acid isoform of E6AP. Domain analysis revealed that the central RLD2 domain of HERC2 and a domain near the N terminus of E6AP were required for the interaction. Full-length HERC2 or the isolated RLD2 domain of HERC2 stimulated the E3 activity of E6AP in autoubiquitination and in ubiquitination of an E6AP substrate. Stimulation of E6AP did not require catalytically active HERC2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21493713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Fang, N. N., Ng, A. H. M., Measday, V., Mayor, T. <strong>Hul5 HECT ubiquitin ligase plays a major role in the ubiquitylation and turnover of cytosolic misfolded proteins.</strong> Nature Cell Biol. 13: 1344-1352, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21983566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21983566</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21983566[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ncb2343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21983566">Fang et al. (2011)</a> found that Hul5, a yeast homolog of UBE3A, was required for ubiquitylation of misfolded proteins and maintenance of cell fitness after heat-shock treatment. Fluorescence microscopy showed that redistribution of Hul5 from the nucleus to the cytoplasm was important for ubiquitylation of misfolded proteins in the heat-shock response. Pulse-chase experiments revealed that Hul5 targeted misfolded low-solubility cytosolic proteins for degradation through ubiquitylation, independent of chaperones of the SSA subfamily of Hsp70 proteins (see <a href="/entry/140550">140550</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21983566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using in vivo mouse genetics, <a href="#18" class="mim-tip-reference" title="Krishnan, V., Stoppel, D. C., Nong, Y., Johnson, M. A., Nadler, M. J. S., Ozkaynak, E., Teng, B. L., Nagakura, I., Mohammad, F., Silva, M. A., Peterson, S., Cruz, T. J., Kasper, E. M., Arnaout, R., Anderson, M. P. <strong>Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1.</strong> Nature 543: 507-512, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28297715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28297715</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28297715[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature21678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28297715">Krishnan et al. (2017)</a> showed that increasing UBE3A in the nucleus downregulated the glutamatergic synapse organizer Cbln1 (<a href="/entry/600432">600432</a>), which is needed for sociability in mice. Epileptic seizures also repressed Cbln1 and exposed sociability impairments in mice with asymptomatic increases in UBE3A. This Ube3a-seizure synergy mapped to glutamate neurons of the midbrain ventral tegmental area (VTA), where Cbln1 deletions impaired sociability and weakened glutamatergic transmission. <a href="#18" class="mim-tip-reference" title="Krishnan, V., Stoppel, D. C., Nong, Y., Johnson, M. A., Nadler, M. J. S., Ozkaynak, E., Teng, B. L., Nagakura, I., Mohammad, F., Silva, M. A., Peterson, S., Cruz, T. J., Kasper, E. M., Arnaout, R., Anderson, M. P. <strong>Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1.</strong> Nature 543: 507-512, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28297715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28297715</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28297715[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature21678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28297715">Krishnan et al. (2017)</a> provided preclinical evidence that viral vector-based chemogenetic activation of, or restoration of Cbln1 in, VTA glutamatergic neurons reverses the sociability deficits induced by Ube3a and/or seizures. <a href="#18" class="mim-tip-reference" title="Krishnan, V., Stoppel, D. C., Nong, Y., Johnson, M. A., Nadler, M. J. S., Ozkaynak, E., Teng, B. L., Nagakura, I., Mohammad, F., Silva, M. A., Peterson, S., Cruz, T. J., Kasper, E. M., Arnaout, R., Anderson, M. P. <strong>Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1.</strong> Nature 543: 507-512, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28297715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28297715</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28297715[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature21678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28297715">Krishnan et al. (2017)</a> concluded that gene and seizure interactions in VTA glutamatergic neurons impair sociability by downregulating Cbln1, a key node in the protein interaction network of autism genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28297715" 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="#41" class="mim-tip-reference" title="Yi, J. J., Paranjape, S. R., Walker, M. P., Choudhury, R., Wolter, J. M., Fragola, G., Emanuele, M. J., Major, M. B., Zylka, M. J. <strong>The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/beta-catenin pathway by inhibiting the proteasome.</strong> J. Biol. Chem. 292: 12503-12515, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28559284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28559284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28559284[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M117.788448" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28559284">Yi et al. (2017)</a> found that UBE3A interacted with multiple proteasome subunits located along 1 side of the 19S regulatory particle, including 8 core proteasome subunits (e.g., PSMD2; <a href="/entry/606223">606223</a>), in HEK293T cells. Interaction with UBE3A increased ubiquitination of proteasome subunits and reduced their abundance and activity, leading to activation of Wnt (see <a href="/entry/606359">606359</a>) signaling through stabilization and nuclear accumulation of beta-catenin (CTNNB1; <a href="/entry/116806">116806</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28559284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Sun, A. X., Yuan, Q., Fukuda, M., Yu, W., Yan, H., Lim, G. G. Y., Nai, M. H., D'Agostino, G. A., Tran, H.-D., Itahana, Y., Wang, D., Lokman, H., and 13 others. <strong>Potassium channel dysfunction in human neuronal models of Angelman syndrome.</strong> Science 366: 1486-1492, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31857479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31857479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31857479[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aav5386" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31857479">Sun et al. (2019)</a> used human neurons and brain organoids to demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium (BK) channels. <a href="#34" class="mim-tip-reference" title="Sun, A. X., Yuan, Q., Fukuda, M., Yu, W., Yan, H., Lim, G. G. Y., Nai, M. H., D'Agostino, G. A., Tran, H.-D., Itahana, Y., Wang, D., Lokman, H., and 13 others. <strong>Potassium channel dysfunction in human neuronal models of Angelman syndrome.</strong> Science 366: 1486-1492, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31857479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31857479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31857479[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aav5386" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31857479">Sun et al. (2019)</a> provided evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. BK antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an Angelman syndrome mouse model. <a href="#34" class="mim-tip-reference" title="Sun, A. X., Yuan, Q., Fukuda, M., Yu, W., Yan, H., Lim, G. G. Y., Nai, M. H., D'Agostino, G. A., Tran, H.-D., Itahana, Y., Wang, D., Lokman, H., and 13 others. <strong>Potassium channel dysfunction in human neuronal models of Angelman syndrome.</strong> Science 366: 1486-1492, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31857479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31857479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31857479[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aav5386" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31857479">Sun et al. (2019)</a> concluded that their findings suggested that BK channelopathy underlies epilepsy in AS and supported the use of human cells to model human developmental diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31857479" 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>Imprinting of UBE3A</em></strong></p><p>
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As diagrammed by <a href="#24" class="mim-tip-reference" title="Matsuura, T., Sutcliffe, J. S., Fang, P., Galjaard, R.-J., Jiang, Y., Benton, C. S., Rommens, J. M., Beaudet, A. L. <strong>De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome.</strong> Nature Genet. 15: 74-77, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988172</a>] [<a href="https://doi.org/10.1038/ng0197-74" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988172">Matsuura et al. (1997)</a> in their Figure 1, UBE3A was found to lie in the Angelman syndrome (AS; <a href="/entry/105830">105830</a>) region of proximal chromosome 15q defined by the breakpoint of an interstitial deletion on the centromeric side and the breakpoint in a familial t(14;15) on the telomeric side. The region is telomeric to the Prader-Willi syndrome (PWS; <a href="/entry/176270">176270</a>) region which contains the SNRPN gene (<a href="/entry/182279">182279</a>). RT-PCR analysis of UBE3A for imprinted expression in cultured human fibroblasts and lymphoblasts from AS and PWS patients with large deletions using primers in exons 9 and 10 indicated biallelic expression, suggesting that UBE3A was an unlikely candidate locus for AS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8988172" 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="#36" class="mim-tip-reference" title="Vu, T. H., Hoffman, A. R. <strong>Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain. (Letter)</strong> Nature Genet. 17: 12-13, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288087</a>] [<a href="https://doi.org/10.1038/ng0997-12" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288087">Vu and Hoffman (1997)</a> and <a href="#29" class="mim-tip-reference" title="Rougeulle, C., Glatt, H., Lalande, M. <strong>The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. (Letter)</strong> Nature Genet. 17: 14-15, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288088</a>] [<a href="https://doi.org/10.1038/ng0997-14" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288088">Rougeulle et al. (1997)</a> showed that imprinting of the UBE3A gene is restricted to brain. Its expression is biallelic in fibroblasts, lymphoblasts, heart, kidney, and other tissues. This finding is consistent with the clinical manifestations of AS and the postmortem findings, both of which suggest that the brain is the major organ affected in this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9288087+9288088" 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="#2" class="mim-tip-reference" title="Albrecht, U., Sutcliffe, J. S., Cattanach, B. M., Beechey, C. V., Armstrong, D., Eichele, G., Beaudet, A. L. <strong>Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons.</strong> Nature Genet. 17: 75-78, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288101</a>] [<a href="https://doi.org/10.1038/ng0997-75" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288101">Albrecht et al. (1997)</a> used mice with partial paternal uniparental disomy (UPD) encompassing Ube3a to differentiate maternal and paternal expression. They found by in situ hybridization that expression of Ube3a in Purkinje cells, hippocampal neurons, and mitral cells of the olfactory bulb in UPD mice was markedly reduced compared to non-UPD littermates. In contrast, expression of Ube3a in other regions of the brain was reduced only moderately or not at all in UPD mice. The major phenotypic features of AS correlate with the loss of maternal-specific expression of Ube3a in hippocampus and cerebellum as revealed in this mouse model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9288101" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To determine possible epigenetic effects on expression within duplicated 15q11-q13 regions, <a href="#10" class="mim-tip-reference" title="Herzing, L. B. K., Cook, E. H., Ledbetter, D. H. <strong>Allele-specific expression analysis by RNA-FISH demonstrates preferential maternal expression of UBE3A and imprint maintenance within 15q11- q13 duplications.</strong> Hum. Molec. Genet. 11: 1707-1718, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12095913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12095913</a>] [<a href="https://doi.org/10.1093/hmg/11.15.1707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12095913">Herzing et al. (2002)</a> used RNA-FISH to observe gene expression. RNA-FISH, unlike RT-PCR, is polymorphism-independent and detects relative levels of expression at each allele. Unamplified, gene-specific RNA signals were detected using cDNA probes. Subsequent DNA-FISH confirmed RNA signals and assigned parental origin by colocalization of genomic probes. SNRPN (<a href="/entry/182279">182279</a>) and NDN (<a href="/entry/602117">602117</a>) expression was detected primarily from paternal alleles. However, maternal UBE3A signals were consistently larger than paternal signals in normal fibroblasts, neural precursor cells, on one or both maternal alleles in a cell line carrying a maternal interstitial duplication, and on both alleles of a maternally derived marker(15) chromosome. Excess total maternal UBE3A RNA was confirmed by Northern blot analysis of cell lines carrying 15q11-q13 duplications or triplications. The authors concluded that UBE3A is imprinted in fibroblasts, lymphoblasts and neural-precursor cells; that allelic imprint status is maintained in the majority of cells upon duplication both in cis and in trans; and that alleles on specific types of duplications may exhibit an increase in expression levels/loss of expression constraints. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12095913" 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="#40" class="mim-tip-reference" title="Yamasaki, K., Joh, K., Ohta, T., Masuzaki, H., Ishimaru, T., Mukai, T., Niikawa, N., Ogawa, M., Wagstaff, J., Kishino, T. <strong>Neurons but not glial cells show reciprocal imprinting of sense and antisense transcripts of Ube3a.</strong> Hum. Molec. Genet. 12: 837-847, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12668607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12668607</a>] [<a href="https://doi.org/10.1093/hmg/ddg106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12668607">Yamasaki et al. (2003)</a> analyzed Ube3a imprinting status in embryonic mouse cortical cell cultures. RT-PCR and immunofluorescence were performed to determine the allelic expression of the gene. The sense transcript was expressed maternally in neurons but biallelically in glial cells in the embryonic brain, whereas the antisense transcript (UBE3AATS, or SNHG14; <a href="/entry/616259">616259</a>) was expressed only in neurons and only from the paternal allele. <a href="#40" class="mim-tip-reference" title="Yamasaki, K., Joh, K., Ohta, T., Masuzaki, H., Ishimaru, T., Mukai, T., Niikawa, N., Ogawa, M., Wagstaff, J., Kishino, T. <strong>Neurons but not glial cells show reciprocal imprinting of sense and antisense transcripts of Ube3a.</strong> Hum. Molec. Genet. 12: 837-847, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12668607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12668607</a>] [<a href="https://doi.org/10.1093/hmg/ddg106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12668607">Yamasaki et al. (2003)</a> concluded that reciprocal imprinting of sense and antisense transcripts present only in neurons suggests a neuron-specific imprinting mechanism that is related to the lineage determination of neural stem cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12668607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Dindot, S. V., Antalffy, B. A., Bhattacharjee, M. B., Beaudet, A. L. <strong>The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology.</strong> Hum. Molec. Genet. 17: 111-118, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17940072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17940072</a>] [<a href="https://doi.org/10.1093/hmg/ddm288" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17940072">Dindot et al. (2008)</a> found that transgenic mice expressing fluorescence-tagged Ube3a showed expression preferentially from the maternal allele in central neurons, but biallelic expression in glial cells. Expression was detected in both neuronal cell nuclei and synapses. Mice with maternal deficiency for Ube3a had abnormal dendritic spine morphology and density on cerebellar Purkinje cells and on pyramidal neurons of the hippocampus and cortex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17940072" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Meng, L., Person, R. E., Huang, W., Zhu, P. J., Costa-Mattioli, M., Beaudet, A. L. <strong>Truncation of Ube3a-ATS unsilences paternal Ube3a and ameliorates behavioral defects in the Angelman syndrome mouse model.</strong> PLoS Genet. 9: e1004039, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24385930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24385930</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24385930[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/10.1371/journal.pgen.1004039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24385930">Meng et al. (2013)</a> noted that the promoters of both paternal and maternal UBE3A remain unmethylated in human brain. They found that the promoter regions of both maternal and paternal mouse Ube3a alleles were transcriptionally active. Chromatin immunoprecipitation analysis, followed by allele-specific PCR and sequencing, showed that only the transcriptionally active paternal allele of the Snrpn promoter in associated with the transcription preinitiation complex (PIC), whereas both parental alleles of the Ube3a promoter were detected in the same fraction with PIC. Strand-specific microarray data revealed a significant decrease of Ube3aats RNA around intron 4 of Ube3a, near the region where paternal Ube3a pre-mRNA becomes suppressed. <a href="#25" class="mim-tip-reference" title="Meng, L., Person, R. E., Huang, W., Zhu, P. J., Costa-Mattioli, M., Beaudet, A. L. <strong>Truncation of Ube3a-ATS unsilences paternal Ube3a and ameliorates behavioral defects in the Angelman syndrome mouse model.</strong> PLoS Genet. 9: e1004039, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24385930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24385930</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24385930[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/10.1371/journal.pgen.1004039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24385930">Meng et al. (2013)</a> proposed a 'transcriptional collision' model for suppression of paternal Ube3a expression, in which both Ube3a sense and antisense RNAs are transcribed head-to-head at a relatively high level until the polymerases reach intron 4, where both drop to a lower level. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24385930" 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>Effects of MECP2 Deficiency on UBE3A Expression</em></strong></p><p>
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Rett syndrome (<a href="/entry/312750">312750</a>), an X-linked dominant disorder caused by MECP2 (<a href="/entry/300005">300005</a>) mutations, and Angelman syndrome have phenotypic and genetic overlap with autism (<a href="/entry/209850">209850</a>). <a href="#30" class="mim-tip-reference" title="Samaco, R. C., Hogart, A., LaSalle, J. M. <strong>Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3.</strong> Hum. Molec. Genet. 14: 483-492, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15615769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15615769</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15615769[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddi045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15615769">Samaco et al. (2005)</a> tested the hypothesis that MECP2 deficiency may affect the level of expression of UBE3A and neighboring autism candidate gene GABRB3 (<a href="/entry/137192">137192</a>) without necessarily affecting imprinted expression. Multiple quantitative methods revealed significant defects in UBE3A expression in 2 different Mecp2-deficient mouse strains, as well as Rett, Angelman, and autism brain samples compared with control samples. Although no difference was observed in the allelic expression of several imprinted transcripts in Mecp2-null mouse brain, Ube3a sense expression was significantly reduced, consistent with the decrease in protein. The nonimprinted GABRB3 gene also showed significantly reduced expression in multiple Rett, Angelman, and autism brain samples, as well as Mecp2-deficient mice. <a href="#30" class="mim-tip-reference" title="Samaco, R. C., Hogart, A., LaSalle, J. M. <strong>Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3.</strong> Hum. Molec. Genet. 14: 483-492, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15615769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15615769</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15615769[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddi045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15615769">Samaco et al. (2005)</a> proposed an overlapping pathway of gene dysregulation within chromosome 15q11-q13 in Rett syndrome, Angelman syndrome, and autism, and implicated MECP2 in the regulation of UBE3A and GABRB3 expression in the postnatal mammalian brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15615769" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Makedonski, K., Abuhatzira, L., Kaufman, Y., Razin, A., Shemer, R. <strong>MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression.</strong> Hum. Molec. Genet. 14: 1049-1058, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15757975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15757975</a>] [<a href="https://doi.org/10.1093/hmg/ddi097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15757975">Makedonski et al. (2005)</a> showed that UBE3A mRNA and protein were significantly reduced in human and mouse MECP2-deficient brains. Reduced UBE3A level was associated with biallelic production of the UBE3A antisense RNA. In addition, MECP2 deficiency resulted in elevated histone H3 acetylation and H3(K4) methylation and reduced H3(K9) methylation at the PWS/AS imprinting center, with no effect on DNA methylation or SNRPN expression. <a href="#21" class="mim-tip-reference" title="Makedonski, K., Abuhatzira, L., Kaufman, Y., Razin, A., Shemer, R. <strong>MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression.</strong> Hum. Molec. Genet. 14: 1049-1058, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15757975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15757975</a>] [<a href="https://doi.org/10.1093/hmg/ddi097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15757975">Makedonski et al. (2005)</a> concluded that MECP2 deficiency causes epigenetic aberrations at the PWS imprinting center. These changes in histone modifications may result in loss of imprinting of the UBE3A antisense gene in the brain, increase in UBE3A antisense RNA level and, consequently, reduction in UBE3A production. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15757975" 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="Huang, L., Kinnucan, E., Wang, G., Beaudenon, S., Howley, P. M., Huibregtse, J. M., Pavletich, N. P. <strong>Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade.</strong> Science 286: 1321-1326, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10558980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10558980</a>] [<a href="https://doi.org/10.1126/science.286.5443.1321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10558980">Huang et al. (1999)</a> determined that the crystal structure of the catalytic hect domain of E6AP revealed a bilobal structure with a broad catalytic cleft at the junction of the 2 lobes. The cleft consists of conserved residues whose mutation interferes with ubiquitin-thioester bond formation and is the site of Angelman syndrome mutations. The crystal structure of E6AP hect domain bound to the UBCH7 ubiquitin-conjugating (E2) enzyme (<a href="/entry/603721">603721</a>) revealed the determinants of the E2-E3 specificity and provided insights into the transfer of ubiquitin from the E2 to the E3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10558980" 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="#16" class="mim-tip-reference" title="Kishino, T., Lalande, M., Wagstaff, J. <strong>UBE3A/E6-AP mutations cause Angelman syndrome.</strong> Nature Genet. 15: 70-73, 1997. Note: Erratum: Nature Genet. 15: 411 only, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988171</a>] [<a href="https://doi.org/10.1038/ng0197-70" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988171">Kishino et al. (1997)</a> found an inversion that caused Angelman syndrome (AS; <a href="/entry/105830">105830</a>) when transmitted maternally and which disrupted the 5-prime end of the UBE3A gene. They subsequently identified 2 mutations in nondeletion/nonuniparental disomy/nonimprinting mutation (NDUI) AS patients that were predicted to eliminate UBE3A function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8988171" 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="Matsuura, T., Sutcliffe, J. S., Fang, P., Galjaard, R.-J., Jiang, Y., Benton, C. S., Rommens, J. M., Beaudet, A. L. <strong>De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome.</strong> Nature Genet. 15: 74-77, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988172</a>] [<a href="https://doi.org/10.1038/ng0197-74" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988172">Matsuura et al. (1997)</a> identified 4 mutations in the UBE3A gene in AS patients, including a de novo frameshift mutation and a de novo nonsense mutation in exon 3 and 2 missense mutations of less certain significance. The de novo truncating mutations indicated that UBE3A is the AS gene and suggested the possibility of a maternally expressed gene product in addition to the biallelically expressed transcript. The authors commented that intragenic mutation of UBE3A in Angelman syndrome was the first example of a genetic disorder of the ubiquitin-dependent proteolytic pathway in mammals. It may represent an example of a human genetic disorder associated with a locus producing functionally distinct imprinted and biallelically expressed gene products. Precedent for the production of imprinted and nonimprinted transcripts from a single locus exist for insulin-like growth factor-2 (IGF2; <a href="/entry/147470">147470</a>), where 4 promoters, 3 imprinted and 1 biallelically expressed, account for differential expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8988172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Malzac, P., Webber, H., Moncla, A., Graham, J. M., Jr., Kukolich, M., Williams, C., Pagon, R. A., Ramsdell, L. A., Kishino, T., Wagstaff, J. <strong>Mutation analysis of UBE3A in Angelman syndrome patients.</strong> Am. J. Hum. Genet. 62: 1353-1360, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585605</a>] [<a href="https://doi.org/10.1086/301877" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9585605">Malzac et al. (1998)</a> identified UBE3A coding-region mutations detected by SSCP analysis in 13 AS individuals or families. In 2 cases, an identical de novo 5-bp duplication in exon 16 was found. Among the other 11 unique mutations, 8 were small deletions or insertions predicted to cause frameshifts, 1 was a mutation to a stop codon, 1 was a missense mutation, and 1 was predicted to cause insertion of an isoleucine in the hect domain of the UBE3A protein, which functions in E2 binding and ubiquitin transfer. Eight of the cases were familial, and 5 were sporadic. In 2 familial cases and 1 sporadic case, mosaicism for UBE3A mutations was detected: in the mother of 3 AS sons, in the maternal grandfather of 2 AS first cousins, and in the mother of an AS daughter. The frequency with which they detected mutations was 5 (14%) of 35 in sporadic cases and 8 (80%) of 10 in familial cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9585605" 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="Fung, D. C. Y., Yu, B., Cheong, K. F., Smith, A., Trent, R. J. <strong>UBE3A 'mutations' in two unrelated and phenotypically different Angelman syndrome patients.</strong> Hum. Genet. 102: 487-492, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9600250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9600250</a>] [<a href="https://doi.org/10.1007/s004390050727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9600250">Fung et al. (1998)</a> found a functionally insignificant 14-bp deletion in the 3-prime untranslated region of the UBE3A1 gene. The allelic variant was identified in the search for a mutation in a patient with what was thought to be atypical Angelman syndrome. The patient had mental retardation, lack of speech, ataxia, and a 'happy disposition.' A fair complexion, strabismus, and disrupted sleep were also observed. She was considered to be atypical since she was very short in stature and did not have a prominent mandible. In addition, her ataxia was less severe than is typically seen in Angelman syndrome, she did not exhibit inappropriate laughter, and she had normal occiput formation as well as a normal EEG at age 2 years and 6 months. The 14-bp deletion was found in the patient, her normal sib, and her unaffected mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9600250" 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="Fang, P., Lev-Lehman, E., Tsai, T.-F., Matsuura, T., Benton, C. S., Sutcliffe, J. S., Christian, S. L., Kubota, T., Halley, D. J., Meijers-Heijboer, H., Langlois, S., Graham, J. M., Jr., Beuten, J., Willems, P. J., Ledbetter, D. H., Beaudet, A. L. <strong>The spectrum of mutations in UBE3A causing Angelman syndrome.</strong> Hum. Molec. Genet. 8: 129-135, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9887341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9887341</a>] [<a href="https://doi.org/10.1093/hmg/8.1.129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9887341">Fang et al. (1999)</a> sequenced the major coding exons of the UBE3A gene in 56 index patients with a clinical diagnosis of Angelman syndrome and a normal DNA methylation pattern. Disease-causing mutations were identified in 17 of the 56 patients (30%), including 13 truncating mutations, 2 missense mutations, 1 single amino acid deletion, and 1 stop codon mutation which predicted an elongated protein. Mutations were identified in 6 of 8 families (75%) with more than 1 affected individual, and in 11 of 47 isolated cases (23%); no mutation was found in 1 family with 2 sibs, 1 with typical and 1 with atypical phenotype. Mutations were de novo in 9 of the 11 isolated cases. An amino acid polymorphism, ala178 to thr, was identified, and a 3-bp length polymorphism was found in the intron upstream of exon 8. In all informative cases, phenotypic expression was consistent with imprinting, with a normal phenotype when the mutation was on the paternal chromosome and an Angelman syndrome phenotype when the mutation was on the maternal chromosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9887341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Rapakko, K., Kokkonen, H., Leisti, J. <strong>UBE3A gene mutations in Finnish Angelman syndrome patients detected by conformation sensitive gel electrophoresis.</strong> Am. J. Med. Genet. 126A: 248-252, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15054837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15054837</a>] [<a href="https://doi.org/10.1002/ajmg.a.20587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15054837">Rapakko et al. (2004)</a> performed conformation-sensitive gel electrophoresis (CSGE) mutation analysis of the UBE3A coding region in 9 patients with Angelman syndrome who had shown a normal biparental inheritance and methylation pattern of 15q11-q13. They identified disease-causing mutations in 5 of them, including 2 missense mutations: thr106 to pro (<a href="#0006">601623.0006</a>) and ile130 to thr (<a href="#0007">601623.0007</a>). Two patients shared a frameshift deletion of 4 nucleotides in exon 16: 3093delAAGA (<a href="#0008">601623.0008</a>); the fifth patient's mutation was a frameshift resulting from 1930delAG in exon 9 (<a href="#0009">601623.0009</a>). CSGE was found to be a sensitive and simple screening method for mutations in UBE3A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15054837" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Camprubi, C., Guitart, M., Gabau, E., Coll, M. D., Villatoro, S., Oltra, S., Rosello, M., Ferrer, I., Monfort, S., Orellana, C., Martinez, F. <strong>Novel UBE3A mutations causing Angelman syndrome: different parental origin for single nucleotide changes and multiple nucleotide deletions or insertions.</strong> Am. J. Med. Genet. 149A: 343-348, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19213023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19213023</a>] [<a href="https://doi.org/10.1002/ajmg.a.32659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19213023">Camprubi et al. (2009)</a> analyzed the UBE3A gene in a total of 237 AS patients with normal methylation patterns and identified 11 mutations, in 5 (13.2%) of 38 stringently selected patients and in 6 (3%) of 199 patients for whom clinical criteria were loosely applied, respectively. There was significant association between inheritance and type of mutation, with 5 single nucleotide changes being inherited from a healthy mother, whereas 4 of 5 multiple nucleotide deletions or insertions arose de novo in the patient (p = 0.02). In 1 case, an inherited mutation was present in the healthy mother, who carried the mutation in mosaic in her blood cells on the paternally derived chromosome. Review of previously published AS mutations confirmed the association with inheritance, with the proportion of multiple nucleotide deletions and insertions occurring de novo almost double that of single nucleotide substitutions (p = 0.015). Noting that only 3 of the 11 UBE3A mutations detected in this study had been previously reported, <a href="#3" class="mim-tip-reference" title="Camprubi, C., Guitart, M., Gabau, E., Coll, M. D., Villatoro, S., Oltra, S., Rosello, M., Ferrer, I., Monfort, S., Orellana, C., Martinez, F. <strong>Novel UBE3A mutations causing Angelman syndrome: different parental origin for single nucleotide changes and multiple nucleotide deletions or insertions.</strong> Am. J. Med. Genet. 149A: 343-348, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19213023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19213023</a>] [<a href="https://doi.org/10.1002/ajmg.a.32659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19213023">Camprubi et al. (2009)</a> suggested that the variability of mutational changes causing AS would increase as new cases were described. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19213023" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#15" class="mim-tip-reference" title="Jiang, Y., Armstrong, D., Albrecht, U., Atkins, C. M., Noebels, J. L., Eichele, G., Sweatt, J. D., Beaudet, A. L. <strong>Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation.</strong> Neuron 21: 799-811, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9808466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9808466</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80596-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9808466">Jiang et al. (1998)</a> generated transgenic mice with the maternal or paternal UBE3A genes knocked out and compared them with their wildtype (m+/p+) littermates. Mice with paternal deficiency (m+/p-) were essentially similar to wildtype mice. The phenotype of mice with maternal deficiency (m-/p+) resembles that of human AS with motor dysfunction, inducible seizures, and a context-dependent learning deficit. The absence of detectable expression of UBE3a in hippocampal neurons and Purkinje cells in m-/p+ mice, indicating imprinting with silencing of the paternal allele, correlated well with the neurologic and cognitive impairments. Long-term potentiation in the hippocampus was severely impaired. The cytoplasmic abundance of p53 was found to be greatly increased in Purkinje cells and in a subset of hippocampal neurons in m-/p+ mice, as well as in a deceased AS patient. <a href="#15" class="mim-tip-reference" title="Jiang, Y., Armstrong, D., Albrecht, U., Atkins, C. M., Noebels, J. L., Eichele, G., Sweatt, J. D., Beaudet, A. L. <strong>Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation.</strong> Neuron 21: 799-811, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9808466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9808466</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80596-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9808466">Jiang et al. (1998)</a> suggested that failure of Ube3a to ubiquitinate target proteins and promote their degradation could be a key aspect of the pathogenesis of AS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9808466" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Wu, Y., Bolduc, F. V., Bell, K., Tully, T., Fang, Y., Sehgal, A., Fischer, J. A. <strong>A Drosophila model for Angelman syndrome.</strong> Proc. Nat. Acad. Sci. 105: 12399-12404, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18701717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18701717</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18701717[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0805291105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18701717">Wu et al. (2008)</a> determined that the Drosophila Dube3a gene is the counterpart of the human UBE3A gene. In normal flies, Dube3a showed ubiquitous and cytoplasmic expression in the central nervous system starting early in embryogenesis. Expression of Dube3a was enriched in the adult mushroom body, the seat of learning and memory. Dube3a-null flies appeared normal externally, but showed abnormal locomotive behavior and circadian rhythms and defective long-term memory. Mutant flies that overexpressed Dube3a in the nervous system also showed locomotion defects, as well as aberrant eye and wing morphology. The locomotion defects in flies with both null and overexpression of Dube3a were dependent on ubiquitin ligase activity. Introduction of missense UBE3A mutations into Dube3a behaved as loss-of-function mutations. <a href="#38" class="mim-tip-reference" title="Wu, Y., Bolduc, F. V., Bell, K., Tully, T., Fang, Y., Sehgal, A., Fischer, J. A. <strong>A Drosophila model for Angelman syndrome.</strong> Proc. Nat. Acad. Sci. 105: 12399-12404, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18701717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18701717</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18701717[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0805291105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18701717">Wu et al. (2008)</a> stated that the simplest model for Angelman syndrome suggests that in the absence of UBE3A, particular substrates fail to be ubiquitinated and proteasomally degraded, accumulate in the brain, and interfere with brain function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18701717" 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="#9" class="mim-tip-reference" title="Greer, P. L., Hanayama, R., Bloodgood, B. L., Mardinly, A. R., Lipton, D. M., Flavell, S. W., Kim, T.-K., Griffith, E. C., Waldon, Z., Maehr, R., Ploegh, H. L., Chowdhury, S., Worley, P. F., Steen, J., Greenberg, M. E. <strong>The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating Arc.</strong> Cell 140: 704-716, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20211139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20211139</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20211139[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2010.01.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20211139">Greer et al. (2010)</a> found that neurons cultured from Ube3a-knockout mice showed reduced surface expression of Glur1 at synapses compared with wildtype neurons. The effect appeared to be specific to AMPARs, since no changes were observed in the surface expression of NMDARs (see GRIN1; <a href="/entry/138249">138249</a>). Whole-cell recordings of CA1 hippocampal pyramidal neurons revealed weakened AMPAR-mediated currents, but not NMDAR-mediated currents, and reduced frequency of miniature excitatory postsynaptic currents in Ube3a-knockout neurons compared with wildtype neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20211139" 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="#33" class="mim-tip-reference" title="Smith, S. E. P., Zhou, Y.-D., Zhang, G., Jin, Z., Stoppel, D. C., Anderson, M. P. <strong>Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice.</strong> Sci. Transl. Med. 3: 103ra97, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21974935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21974935</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21974935[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/scitranslmed.3002627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21974935">Smith et al. (2011)</a> stated that maternally inherited duplications and triplications in the region of chromosome 15q containing the UBE3A gene are among the most common genomic copy number variations identified in patients with autism spectrum disorder (see <a href="/entry/608636">608636</a>). They developed transgenic mice with double or triple the dosage of the long form of Ube3a in neurons. Mice with 3 copies of the Ube3a gene showed defective social interaction, reduced socially elicited ultrasonic vocalization, and increased repetitive grooming behavior. Transgenic mice carrying 2 copies of Ube3a showed a more limited phenotype. Increased Ube3a gene dosage impaired excitatory synaptic transmission in layer-2/3 pyramidal neurons, with reduced presynaptic glutamate release probability and suppressed coupling of synaptic currents to firing of postsynaptic action potentials. Transgenic mice with double or triple dosage of the inactive short form of Ube3a were similar to wildtype mice in all measures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21974935" 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="#11" class="mim-tip-reference" title="Huang, H.-S., Allen, J. A., Mabb, A. M., King, I. F., Miriyala, J., Taylor-Blake, B., Sciaky, N., Dutton, J. W., Jr., Lee, H.-M., Chen, X., Jin, J., Bridges, A. S., Zylka, M. J., Roth, B. L., Philpot, B. D. <strong>Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons.</strong> Nature 481: 185-189, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22190039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22190039</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22190039[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22190039">Huang et al. (2012)</a> used an unbiased, high-content screen in primary cortical neurons from mice, to identify 12 topoisomerase I (<a href="/entry/126420">126420</a>) inhibitors and 4 topoisomerase II (see <a href="/entry/126430">126430</a>) inhibitors that unsilence the paternal Ube3a allele. These drugs included topotecan, irinotecan, etoposide, and dexrazoxane. At nanomolar concentrations, topotecan upregulated catalytically active UBE3A in neurons from maternal Ube3a-null mice. Topotecan concomitantly downregulated expression of the Ube3a antisense transcript that overlaps the paternal copy of Ube3a. These results indicated that topotecan unsilences Ube3a in cis by reducing transcription of an imprinted antisense RNA. When administered in vivo, topotecan unsilenced the paternal Ube3a allele in several regions of the nervous system, including neurons in the hippocampus, neocortex, striatum, cerebellum, and spinal cord. Paternal expression of Ube3a remained elevated in a subset of spinal cord neurons for at least 12 weeks after cessation of topotecan treatment, indicating that transient topoisomerase inhibition can have enduring effects on gene expression. <a href="#11" class="mim-tip-reference" title="Huang, H.-S., Allen, J. A., Mabb, A. M., King, I. F., Miriyala, J., Taylor-Blake, B., Sciaky, N., Dutton, J. W., Jr., Lee, H.-M., Chen, X., Jin, J., Bridges, A. S., Zylka, M. J., Roth, B. L., Philpot, B. D. <strong>Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons.</strong> Nature 481: 185-189, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22190039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22190039</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22190039[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22190039">Huang et al. (2012)</a> concluded that, although potential off-target effects remain to be investigated, their findings suggest a therapeutic strategy for reactivating the functional but dormant allele of Ube3a in patients with Angelman syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22190039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Meng, L., Person, R. E., Huang, W., Zhu, P. J., Costa-Mattioli, M., Beaudet, A. L. <strong>Truncation of Ube3a-ATS unsilences paternal Ube3a and ameliorates behavioral defects in the Angelman syndrome mouse model.</strong> PLoS Genet. 9: e1004039, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24385930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24385930</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24385930[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/10.1371/journal.pgen.1004039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24385930">Meng et al. (2013)</a> observed that imprinting of UBE3A expression is not associated with differential DNA methylation at the paternal UBE3A promoter region, but is due to paternal expression of UBE3AATS. Mice heterozygous for Ube3a deletion show characteristics similar to AS, including cognitive and motor coordination defects and impaired long-term potentiation. <a href="#25" class="mim-tip-reference" title="Meng, L., Person, R. E., Huang, W., Zhu, P. J., Costa-Mattioli, M., Beaudet, A. L. <strong>Truncation of Ube3a-ATS unsilences paternal Ube3a and ameliorates behavioral defects in the Angelman syndrome mouse model.</strong> PLoS Genet. 9: e1004039, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24385930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24385930</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24385930[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/10.1371/journal.pgen.1004039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24385930">Meng et al. (2013)</a> found that premature termination of Ube3aats via insertion of a poly(A) cassette activated expression of Ube3a from the paternal chromosome and ameliorated many disease-related symptoms in AS mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24385930" 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 transcriptome analysis, <a href="#8" class="mim-tip-reference" title="Furumai, R., Tamada, K., Liu, X., Takumi, T. <strong>UBE3A regulates the transcription of IRF, an antiviral immunity.</strong> Hum. Molec. Genet. 28: 1947-1958, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30690483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30690483</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30690483[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddz019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30690483">Furumai et al. (2019)</a> found that genes downstream of interferon regulatory factors (IRFs; see <a href="/entry/147575">147575</a>) were enriched in brains of Ube3a-deficient AS mice. In vitro analysis indicated that Ube3a interacted with IRFs and promoted IRF-dependent transcriptional activities at least partially through its E3 ubiquitin ligase activity in AS mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30690483" 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 2 brothers with Angelman syndrome (AS; <a href="/entry/105830">105830</a>), <a href="#16" class="mim-tip-reference" title="Kishino, T., Lalande, M., Wagstaff, J. <strong>UBE3A/E6-AP mutations cause Angelman syndrome.</strong> Nature Genet. 15: 70-73, 1997. Note: Erratum: Nature Genet. 15: 411 only, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988171</a>] [<a href="https://doi.org/10.1038/ng0197-70" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988171">Kishino et al. (1997)</a> found an A-to-G transition in the UBE3A gene that created a new 3-prime splice junction 7-bp upstream from the normal splice junction. The mutation was predicted to cause a frameshift and premature termination of translation. SSCP analysis of products derived with primers flanking exon 10 showed an abnormal band that was also present in their normal mother but not in their father. The normal phenotype of the mother was presumably a consequence of her having inherited the mutation from her father. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8988171" 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">rs587784512 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587784512;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=rs587784512" 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=rs587784512" 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=RCV000147864 OR RCV003229812" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000147864, RCV003229812" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000147864...</a>
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<p><a href="#24" class="mim-tip-reference" title="Matsuura, T., Sutcliffe, J. S., Fang, P., Galjaard, R.-J., Jiang, Y., Benton, C. S., Rommens, J. M., Beaudet, A. L. <strong>De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome.</strong> Nature Genet. 15: 74-77, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988172</a>] [<a href="https://doi.org/10.1038/ng0197-74" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988172">Matsuura et al. (1997)</a> studied 10 patients meeting standard clinical diagnostic criteria for Angelman syndrome (AS; <a href="/entry/105830">105830</a>) and 1 with possible Angelman syndrome, all having a normal methylation pattern at SNRPN (<a href="/entry/182279">182279</a>). One of the 11 patients was found to have a 2-bp deletion (1344delAG), resulting in a frameshift and premature termination 23 codons downstream. This mutation was not present in either parent. <a href="#7" class="mim-tip-reference" title="Fung, D. C. Y., Yu, B., Cheong, K. F., Smith, A., Trent, R. J. <strong>UBE3A 'mutations' in two unrelated and phenotypically different Angelman syndrome patients.</strong> Hum. Genet. 102: 487-492, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9600250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9600250</a>] [<a href="https://doi.org/10.1007/s004390050727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9600250">Fung et al. (1998)</a> found this mutation in a patient with typical Angelman syndrome. Restriction analysis of parental amplicons with XbaI and EcoRI demonstrated that the allele was not carried by either parent. Nonpaternity was excluded on the basis of genotyping with 5 highly polymorphic markers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9600250+8988172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 ANGELMAN SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs111033594 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033594;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs111033594?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs111033594" 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=rs111033594" 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=RCV000008430" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008430" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008430</a>
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<p>In a patient with Angelman syndrome (AS; <a href="/entry/105830">105830</a>), <a href="#24" class="mim-tip-reference" title="Matsuura, T., Sutcliffe, J. S., Fang, P., Galjaard, R.-J., Jiang, Y., Benton, C. S., Rommens, J. M., Beaudet, A. L. <strong>De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome.</strong> Nature Genet. 15: 74-77, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988172</a>] [<a href="https://doi.org/10.1038/ng0197-74" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988172">Matsuura et al. (1997)</a> identified an arg417-to-ter (R417X) nonsense mutation. This mutation resulted in loss of a TaqI restriction enzyme site. An analysis of the family revealed that this was a de novo mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8988172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 ANGELMAN SYNDROME</strong>
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UBE3A, TRP768TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs111033595 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033595;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=rs111033595" 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=rs111033595" 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=RCV000008431" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008431" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008431</a>
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<p>In a family of mixed Ashkenazi and Iraqi Jewish descent, <a href="#35" class="mim-tip-reference" title="Tsai, T.-F., Raas-Rothschild, A., Ben-Neriah, Z., Beaudet, A. L. <strong>Prenatal diagnosis and carrier detection for a point mutation in UBE3A causing Angelman syndrome. (Letter)</strong> Am. J. Hum. Genet. 63: 1561-1563, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9792887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9792887</a>] [<a href="https://doi.org/10.1086/302120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9792887">Tsai et al. (1998)</a> observed 2 children affected with Angelman syndrome (AS; <a href="/entry/105830">105830</a>). Sequence analysis for the 10 major coding exons of UBE3A identified a nonsense mutation in exon 15. The mutation was a G-to-A substitution at nucleotide 2304, which caused a nonsense mutation (trp768 to ter) at the protein level. The mother was heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9792887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 ANGELMAN SYNDROME</strong>
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UBE3A, THR106PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs111033596 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033596;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=rs111033596" 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=rs111033596" 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=RCV000008432" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008432" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008432</a>
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<p>In a patient with Angelman syndrome (AS; <a href="/entry/105830">105830</a>) who had shown a normal biparental inheritance and methylation pattern of 15q11-q13, <a href="#28" class="mim-tip-reference" title="Rapakko, K., Kokkonen, H., Leisti, J. <strong>UBE3A gene mutations in Finnish Angelman syndrome patients detected by conformation sensitive gel electrophoresis.</strong> Am. J. Med. Genet. 126A: 248-252, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15054837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15054837</a>] [<a href="https://doi.org/10.1002/ajmg.a.20587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15054837">Rapakko et al. (2004)</a> identified a 902A-C transversion in exon 9 of the UBE3A gene, resulting in a thr106-to-pro amino acid substitution (T106P). The patient's mother was mosaic for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15054837" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 ANGELMAN SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs111033597 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033597;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=rs111033597" 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=rs111033597" 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=RCV000008433" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008433" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008433</a>
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<p>In a patient with Angelman syndrome (AS; <a href="/entry/105830">105830</a>) who had shown a normal biparental inheritance and methylation pattern of 15q11-q13, <a href="#28" class="mim-tip-reference" title="Rapakko, K., Kokkonen, H., Leisti, J. <strong>UBE3A gene mutations in Finnish Angelman syndrome patients detected by conformation sensitive gel electrophoresis.</strong> Am. J. Med. Genet. 126A: 248-252, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15054837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15054837</a>] [<a href="https://doi.org/10.1002/ajmg.a.20587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15054837">Rapakko et al. (2004)</a> identified a 975T-C transition in exon 9 of the UBE3A gene, resulting in an ile130-to-thr amino acid substitution (I130T). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15054837" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 ANGELMAN SYNDROME</strong>
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UBE3A, 4-BP DEL, 3093AAGA
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000147883 OR RCV000481125 OR RCV000622970 OR RCV001260843" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000147883, RCV000481125, RCV000622970, RCV001260843" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000147883...</a>
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<p>In 2 patients with Angelman syndrome (AS; <a href="/entry/105830">105830</a>) who had shown a normal biparental inheritance and methylation pattern of 15q11-q13, <a href="#28" class="mim-tip-reference" title="Rapakko, K., Kokkonen, H., Leisti, J. <strong>UBE3A gene mutations in Finnish Angelman syndrome patients detected by conformation sensitive gel electrophoresis.</strong> Am. J. Med. Genet. 126A: 248-252, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15054837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15054837</a>] [<a href="https://doi.org/10.1002/ajmg.a.20587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15054837">Rapakko et al. (2004)</a> identified a 4-bp deletion in exon 16 of the UBE3A gene, 3093delAAGA, that resulted in a frameshift and premature termination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15054837" 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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UBE3A, 2-BP DEL, 1930AG
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000147864 OR RCV003229812" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000147864, RCV003229812" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000147864...</a>
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<p>In a patient with Angelman syndrome (AS; <a href="/entry/105830">105830</a>) who had shown a normal biparental inheritance and methylation pattern of 15q11-q13, <a href="#28" class="mim-tip-reference" title="Rapakko, K., Kokkonen, H., Leisti, J. <strong>UBE3A gene mutations in Finnish Angelman syndrome patients detected by conformation sensitive gel electrophoresis.</strong> Am. J. Med. Genet. 126A: 248-252, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15054837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15054837</a>] [<a href="https://doi.org/10.1002/ajmg.a.20587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15054837">Rapakko et al. (2004)</a> identified a 2-bp deletion in exon 9 of the UBE3A gene, 1930delAG, that resulted in a frameshift and premature termination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15054837" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 ANGELMAN SYNDROME</strong>
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UBE3A, 4-BP DUP, EX10, GAGG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2152505917 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2152505917;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=rs2152505917" 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=rs2152505917" 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=RCV000008436" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008436" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008436</a>
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<p>In 2 first cousins with Angelman syndrome (AS; <a href="/entry/105830">105830</a>), <a href="#27" class="mim-tip-reference" title="Molfetta, G. A., Silva, W. A., Jr., Pina-Neto, J. M. <strong>Clinical, cytogenetical, and molecular analyses of Angelman syndrome.</strong> Genet. Counsel. 14: 45-56, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12725589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12725589</a>]" pmid="12725589">Molfetta et al. (2003)</a> identified a duplication of GAGG in exon 10 of the UBE3A gene, which caused a frameshift and premature termination. The mutation was inherited from their asymptomatic mothers. <a href="#26" class="mim-tip-reference" title="Molfetta, G. A., Munoz, M. V. R., Santos, A. C., Silva, W. A., Jr., Wagstaff, J., Pina-Neto, J. M. <strong>Discordant phenotypes in first cousins with UBE3A frameshift mutation.</strong> Am. J. Med. Genet. 127A: 258-262, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15150776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15150776</a>] [<a href="https://doi.org/10.1002/ajmg.a.20723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15150776">Molfetta et al. (2004)</a> reported that these first cousins presented discordant phenotypes. The proband had typical AS features, whereas her cousin had a more severe phenotype with asymmetric spasticity, which originally led to the diagnosis of cerebral palsy, and severe brain malformations on MRI. Because the cousins' grandfather had transmitted the mutation to only 2 of 8 sibs, <a href="#26" class="mim-tip-reference" title="Molfetta, G. A., Munoz, M. V. R., Santos, A. C., Silva, W. A., Jr., Wagstaff, J., Pina-Neto, J. M. <strong>Discordant phenotypes in first cousins with UBE3A frameshift mutation.</strong> Am. J. Med. Genet. 127A: 258-262, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15150776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15150776</a>] [<a href="https://doi.org/10.1002/ajmg.a.20723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15150776">Molfetta et al. (2004)</a> raised the hypothesis of mosaicism for this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12725589+15150776" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 ANGELMAN SYNDROME</strong>
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UBE3A, 15-BP DEL/7-BP INS, NT3240
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000023125" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023125" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023125</a>
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<p>In affected members of large highly consanguineous Tunisian kindred with Angelman syndrome (AS; <a href="/entry/105830">105830</a>), <a href="#1" class="mim-tip-reference" title="Abaied, L., Trabelsi, M., Chaabouni, M., Kharrat, M., Kraoua, L., M'rad, R., Tebib, N., Maazoul, F., Chaabouni, H. <strong>A novel UBE3A truncating mutation in large Tunisian Angelman syndrome pedigree.</strong> Am. J. Med. Genet. 152A: 141-146, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20034088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20034088</a>] [<a href="https://doi.org/10.1002/ajmg.a.33179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20034088">Abaied et al. (2010)</a> identified a heterozygous complex mutation involving the UBE3A gene: a 15-bp deletion and 7-bp insertion (3240_3255delinsAGATGTT) at the same position in exon 16, resulting in a frameshift, premature termination, and likely a nonfunctional protein. There were 14 affected individuals, who were all in the same generation, and all patients inherited the mutation from their carrier mothers, who were 4 sisters. These 4 sisters apparently inherited the mutation from their unaffected father, who was deceased. All patients had a severe form of Angelman syndrome, with mental retardation, motor impairment, seizures, hyperactivity, and frequent laughing. Two had severe microcephaly, which <a href="#1" class="mim-tip-reference" title="Abaied, L., Trabelsi, M., Chaabouni, M., Kharrat, M., Kraoua, L., M'rad, R., Tebib, N., Maazoul, F., Chaabouni, H. <strong>A novel UBE3A truncating mutation in large Tunisian Angelman syndrome pedigree.</strong> Am. J. Med. Genet. 152A: 141-146, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20034088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20034088</a>] [<a href="https://doi.org/10.1002/ajmg.a.33179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20034088">Abaied et al. (2010)</a> postulated could be due to a different homozygous mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20034088" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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Abaied, L., Trabelsi, M., Chaabouni, M., Kharrat, M., Kraoua, L., M'rad, R., Tebib, N., Maazoul, F., Chaabouni, H.
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<strong>A novel UBE3A truncating mutation in large Tunisian Angelman syndrome pedigree.</strong>
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Am. J. Med. Genet. 152A: 141-146, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20034088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20034088</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20034088" 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/ajmg.a.33179" target="_blank">Full Text</a>]
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<a id="Albrecht1997" class="mim-anchor"></a>
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Albrecht, U., Sutcliffe, J. S., Cattanach, B. M., Beechey, C. V., Armstrong, D., Eichele, G., Beaudet, A. L.
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<strong>Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons.</strong>
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Nature Genet. 17: 75-78, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288101</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9288101" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng0997-75" target="_blank">Full Text</a>]
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<a id="Camprubi2009" class="mim-anchor"></a>
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Camprubi, C., Guitart, M., Gabau, E., Coll, M. D., Villatoro, S., Oltra, S., Rosello, M., Ferrer, I., Monfort, S., Orellana, C., Martinez, F.
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<strong>Novel UBE3A mutations causing Angelman syndrome: different parental origin for single nucleotide changes and multiple nucleotide deletions or insertions.</strong>
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Am. J. Med. Genet. 149A: 343-348, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19213023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19213023</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19213023" 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/ajmg.a.32659" target="_blank">Full Text</a>]
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<a id="Dindot2008" class="mim-anchor"></a>
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Dindot, S. V., Antalffy, B. A., Bhattacharjee, M. B., Beaudet, A. L.
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<strong>The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology.</strong>
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Hum. Molec. Genet. 17: 111-118, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17940072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17940072</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17940072" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddm288" target="_blank">Full Text</a>]
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<a id="Fang2011" class="mim-anchor"></a>
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Fang, N. N., Ng, A. H. M., Measday, V., Mayor, T.
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<strong>Hul5 HECT ubiquitin ligase plays a major role in the ubiquitylation and turnover of cytosolic misfolded proteins.</strong>
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Nature Cell Biol. 13: 1344-1352, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21983566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21983566</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21983566[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=21983566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ncb2343" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12207887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12207887</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12207887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0006-291x(02)02040-5" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="38" class="mim-anchor"></a>
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<a id="Wu2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wu, Y., Bolduc, F. V., Bell, K., Tully, T., Fang, Y., Sehgal, A., Fischer, J. A.
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<strong>A Drosophila model for Angelman syndrome.</strong>
|
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Proc. Nat. Acad. Sci. 105: 12399-12404, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18701717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18701717</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18701717[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=18701717" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0805291105" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="39" class="mim-anchor"></a>
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<a id="Yamamoto1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yamamoto, Y., Huibregtse, J. M., Howley, P. M.
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<strong>The human E6-AP gene (UBE3A) encodes three potential protein isoforms generated by differential splicing.</strong>
|
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Genomics 41: 263-266, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9143503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9143503</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9143503" 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/10.1006/geno.1997.4617" target="_blank">Full Text</a>]
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<li>
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<a id="40" class="mim-anchor"></a>
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<a id="Yamasaki2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yamasaki, K., Joh, K., Ohta, T., Masuzaki, H., Ishimaru, T., Mukai, T., Niikawa, N., Ogawa, M., Wagstaff, J., Kishino, T.
|
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<strong>Neurons but not glial cells show reciprocal imprinting of sense and antisense transcripts of Ube3a.</strong>
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Hum. Molec. Genet. 12: 837-847, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12668607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12668607</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12668607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg106" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="41" class="mim-anchor"></a>
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<a id="Yi2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yi, J. J., Paranjape, S. R., Walker, M. P., Choudhury, R., Wolter, J. M., Fragola, G., Emanuele, M. J., Major, M. B., Zylka, M. J.
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<strong>The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/beta-catenin pathway by inhibiting the proteasome.</strong>
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J. Biol. Chem. 292: 12503-12515, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28559284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28559284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28559284[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=28559284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M117.788448" target="_blank">Full Text</a>]
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</p>
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</ol>
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 05/07/2020
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 02/18/2020<br>Ada Hamosh - updated : 03/15/2018<br>Patricia A. Hartz - updated : 3/10/2015<br>Patricia A. Hartz - updated : 1/14/2014<br>Patricia A. Hartz - updated : 11/26/2013<br>Ada Hamosh - updated : 2/7/2012<br>Patricia A. Hartz - updated : 2/25/2011<br>Cassandra L. Kniffin - updated : 1/6/2011<br>Patricia A. Hartz - updated : 12/14/2010<br>Marla J. F. O'Neill - updated : 8/27/2010<br>Patricia A. Hartz - updated : 9/21/2009<br>George E. Tiller - updated : 7/31/2009<br>Cassandra L. Kniffin - updated : 5/28/2009<br>Matthew B. Gross - reorganized : 4/10/2009<br>Patricia A. Hartz - updated : 4/10/2009<br>George E. Tiller - updated : 2/7/2008<br>George E. Tiller - updated : 1/3/2008<br>George E. Tiller - updated : 2/21/2005<br>Carol A. Bocchini - updated : 11/3/2004<br>Victor A. McKusick - updated : 4/14/2004<br>George E. Tiller - updated : 6/18/2003<br>Wilson H. Y. Lo - updated : 4/7/2000<br>Ada Hamosh - updated : 11/11/1999<br>Victor A. McKusick - updated : 2/17/1999<br>Victor A. McKusick - updated : 12/8/1998<br>Clair A. Francomano - updated : 6/26/1998<br>Victor A. McKusick - updated : 6/23/1998<br>Rebekah S. Rasooly - updated : 5/19/1998<br>Victor A. McKusick - updated : 8/28/1997
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</span>
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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 : 1/10/1997
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</span>
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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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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 09/19/2022
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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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alopez : 05/07/2020<br>mgross : 02/18/2020<br>alopez : 03/15/2018<br>mgross : 03/19/2015<br>mcolton : 3/10/2015<br>mgross : 1/14/2014<br>mgross : 12/11/2013<br>mgross : 12/11/2013<br>mcolton : 11/26/2013<br>carol : 9/9/2013<br>alopez : 2/13/2012<br>terry : 2/7/2012<br>mgross : 4/6/2011<br>mgross : 4/6/2011<br>mgross : 4/6/2011<br>terry : 2/25/2011<br>wwang : 1/21/2011<br>ckniffin : 1/6/2011<br>mgross : 1/5/2011<br>terry : 12/14/2010<br>wwang : 8/31/2010<br>terry : 8/27/2010<br>mgross : 10/2/2009<br>terry : 9/21/2009<br>wwang : 8/13/2009<br>terry : 7/31/2009<br>wwang : 6/5/2009<br>ckniffin : 5/28/2009<br>mgross : 4/10/2009<br>terry : 4/10/2009<br>wwang : 2/18/2008<br>terry : 2/7/2008<br>wwang : 1/11/2008<br>terry : 1/3/2008<br>wwang : 6/14/2007<br>terry : 6/13/2007<br>carol : 4/6/2006<br>ckniffin : 3/20/2006<br>wwang : 3/2/2005<br>terry : 2/21/2005<br>carol : 11/3/2004<br>alopez : 4/16/2004<br>terry : 4/14/2004<br>cwells : 6/18/2003<br>alopez : 7/11/2002<br>alopez : 7/11/2002<br>alopez : 7/11/2002<br>alopez : 5/3/2001<br>terry : 4/30/2001<br>carol : 7/6/2000<br>terry : 4/7/2000<br>mgross : 12/2/1999<br>alopez : 11/12/1999<br>terry : 11/11/1999<br>mgross : 2/26/1999<br>mgross : 2/22/1999<br>terry : 2/17/1999<br>dkim : 12/11/1998<br>terry : 12/8/1998<br>carol : 6/26/1998<br>carol : 6/25/1998<br>terry : 6/23/1998<br>psherman : 5/20/1998<br>psherman : 5/19/1998<br>jenny : 9/1/1997<br>terry : 8/28/1997<br>mark : 6/27/1997<br>mark : 6/27/1997<br>mark : 6/27/1997<br>mark : 1/15/1997<br>jenny : 1/14/1997<br>mark : 1/10/1997
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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 class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 601623
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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-PROTEIN LIGASE E3A; UBE3A
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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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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HUMAN PAPILLOMAVIRUS E6-ASSOCIATED PROTEIN; E6AP
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</div>
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<div>
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: UBE3A</em></strong>
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</span>
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</div>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 76880004;
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<strong>ICD10CM:</strong> Q93.51;
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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: 15q11.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 15:25,333,728-25,439,056 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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15q11.2
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<td>
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<span class="mim-font">
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Angelman syndrome
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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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105830
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tbody>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>UBE3A functions as both an E3 ligase in the ubiquitin proteasome pathway and as a transcriptional coactivator. The UBE3A gene is subject to genomic imprinting, with preferential maternal-specific expression in brain and, more specifically, in neurons but not in glia (Dindot et al., 2008). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>E6AP was initially identified as a cellular protein that mediates in vitro association of the human papillomavirus E6 protein with p53 (191170), leading to the ubiquitin-dependent degradation of p53 (Huibregtse et al., 1991; Scheffner et al., 1990). Huibregtse et al. (1993) cloned the E6AP gene and studied the expressed protein's association with p53 and E6. The 865-amino acid E6AP protein has a native molecular mass of approximately 100 kD. </p><p>Yamamoto et al. (1997) noted that UBE3A belongs to a family of functionally related proteins defined by a conserved C-terminal 350-amino acid HECT domain. Using RT-PCR, Yamamoto et al. (1997) identified several UBE3A mRNAs encoding protein isoforms that differed at their N termini. Each mRNA was expressed in all cell lines tested. Kishino and Wagstaff (1998) identified additional alternatively spliced forms of UBE3A mRNA. </p><p>Using VCY2 (BPY2; 400013) as bait in a yeast 2-hybrid screen of a testis cDNA library, followed by RT-PCR of testis mRNA, Wong et al. (2002) cloned UBE3A. The deduced 873-amino acid protein contains a C-terminal HECT domain. Northern blot analysis detected strong expression of 1.4- and 2-kb UBE3A transcripts and weaker expression of 4- and 5-kb transcripts in testis and prostate. The 1.4- and 2-kb transcripts were also detected in small intestine and colon. RT-PCR detected UBE3A expression in ejaculated human sperm. </p><p>Using fractionation analysis, Furumai et al. (2019) showed that Ube3a localized mainly to nuclei of mouse neurons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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<p>Yamamoto et al. (1997) found that the coding region of the UBE3A gene is composed of 10 exons and spans at least 60 kb. The 5-prime UTR is composed of at least 4 exons. </p><p>Kishino and Wagstaff (1998) found that the UBE3A gene has at least 16 exons, including 6 exons that encode the 5-prime UTR. The gene spans approximately 120 kb, with transcription oriented from telomere to centromere. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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<p>UBE3A maps within the critical region for Angelman syndrome (AS; 105830) on chromosome 15q11-q13 (Matsuura et al., 1997). </p><p>Smith et al. (2011) stated that the mouse Ube3a gene maps to a region of chromosome 7 that is syntenic to human chromosome 15. </p><p><strong><em>Pseudogenes</em></strong></p><p>
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Kishino and Wagstaff (1998) mapped 2 processed UBE3A pseudogenes to chromosomes 2 and 21. </p>
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<strong>Gene Function</strong>
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<p>Scheffner et al. (1993) found that E6AP is an E3 ubiquitin-protein ligase. </p><p>Using yeast 2-hybrid and coimmunoprecipitation analyses, Wong et al. (2002) showed that VCY2 interacted with the HECT domain of UBE3A. </p><p>Lu et al. (2009) showed that Ube3a was not essential for viability in Drosophila but that loss of Ube3a activity reduced dendritic branching of sensory neurons in the peripheral nervous system and slowed the growth of terminal dendritic fine processes. Ube3a overexpression in Drosophila decreased dendritic branching, suggesting that maintaining a proper level of UBE3A is critical for normal dendritic patterning. </p><p>Greer et al. (2010) found that neuronal activity elevated the expression of rodent Ube3a transcripts in cultured neurons and in mouse brain, concomitant with elevated surface expression of AMPA-type glutamate receptors (AMPARs) (see GLUR1, or GRIA1; 138248) and increased frequency of miniature excitatory postsynaptic currents. Activity specifically elevated expression of Ube3a transcripts initiating from the highly conserved promoters 1 and 3, which contain binding sites for the activity-related transcription factor Mef2 (MEF2A; 600660). Overexpression, knockdown, and mutation experiments revealed that Ube3a elevated postsynaptic surface expression of Glur1 by downregulating Arc (612461), a mediator of Glur1 endocytosis. Downregulation of Arc by Ube3a required the ubiquitin ligase activity of Ube3a and was blocked by a protease inhibitor. Greer et al. (2010) concluded that UBE3A elevates the surface expression and activity of AMPARs by directing the proteasomal degradation of ARC. </p><p>Margolis et al. (2010) found that Ube3a had a role in degrading the Rhoa (165390) guanine nucleotide exchange factor ephexin-5 (E5, or ARHGEF15; 608504), which regulates synapse formation in developing mouse neurons. Binding of E5 to ephrin receptor Ephb2 (600997) inhibited both the tyrosine kinase activity of Ephb2 and excitatory synapse formation. The E5-Ephb2 interaction was terminated by the binding of ephrin B (see EFNB1; 300035) to Ephb2, which resulted in tyrosine phosphorylation, release, and destabilization of E5 and permitted the formation of excitatory synapses. Degradation of E5 required its binding to Ube3a and was inhibited by an inactive Ube3a mutant or proteasome inhibition. Margolis et al. (2010) found that E5 expression was elevated in a mouse model of Angelman syndrome, suggesting that elevated E5 expression during development may contribute to abnormal cognitive function in Angelman syndrome. </p><p>Using yeast 2-hybrid analysis and coprecipitation analysis of cotransfected and endogenous proteins, Kuhnle et al. (2011) found that the E3 ubiquitin ligase HERC2 interacted with the 852-amino acid isoform of E6AP. Domain analysis revealed that the central RLD2 domain of HERC2 and a domain near the N terminus of E6AP were required for the interaction. Full-length HERC2 or the isolated RLD2 domain of HERC2 stimulated the E3 activity of E6AP in autoubiquitination and in ubiquitination of an E6AP substrate. Stimulation of E6AP did not require catalytically active HERC2. </p><p>Fang et al. (2011) found that Hul5, a yeast homolog of UBE3A, was required for ubiquitylation of misfolded proteins and maintenance of cell fitness after heat-shock treatment. Fluorescence microscopy showed that redistribution of Hul5 from the nucleus to the cytoplasm was important for ubiquitylation of misfolded proteins in the heat-shock response. Pulse-chase experiments revealed that Hul5 targeted misfolded low-solubility cytosolic proteins for degradation through ubiquitylation, independent of chaperones of the SSA subfamily of Hsp70 proteins (see 140550). </p><p>Using in vivo mouse genetics, Krishnan et al. (2017) showed that increasing UBE3A in the nucleus downregulated the glutamatergic synapse organizer Cbln1 (600432), which is needed for sociability in mice. Epileptic seizures also repressed Cbln1 and exposed sociability impairments in mice with asymptomatic increases in UBE3A. This Ube3a-seizure synergy mapped to glutamate neurons of the midbrain ventral tegmental area (VTA), where Cbln1 deletions impaired sociability and weakened glutamatergic transmission. Krishnan et al. (2017) provided preclinical evidence that viral vector-based chemogenetic activation of, or restoration of Cbln1 in, VTA glutamatergic neurons reverses the sociability deficits induced by Ube3a and/or seizures. Krishnan et al. (2017) concluded that gene and seizure interactions in VTA glutamatergic neurons impair sociability by downregulating Cbln1, a key node in the protein interaction network of autism genes. </p><p>Yi et al. (2017) found that UBE3A interacted with multiple proteasome subunits located along 1 side of the 19S regulatory particle, including 8 core proteasome subunits (e.g., PSMD2; 606223), in HEK293T cells. Interaction with UBE3A increased ubiquitination of proteasome subunits and reduced their abundance and activity, leading to activation of Wnt (see 606359) signaling through stabilization and nuclear accumulation of beta-catenin (CTNNB1; 116806). </p><p>Sun et al. (2019) used human neurons and brain organoids to demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium (BK) channels. Sun et al. (2019) provided evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. BK antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an Angelman syndrome mouse model. Sun et al. (2019) concluded that their findings suggested that BK channelopathy underlies epilepsy in AS and supported the use of human cells to model human developmental diseases. </p><p><strong><em>Imprinting of UBE3A</em></strong></p><p>
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As diagrammed by Matsuura et al. (1997) in their Figure 1, UBE3A was found to lie in the Angelman syndrome (AS; 105830) region of proximal chromosome 15q defined by the breakpoint of an interstitial deletion on the centromeric side and the breakpoint in a familial t(14;15) on the telomeric side. The region is telomeric to the Prader-Willi syndrome (PWS; 176270) region which contains the SNRPN gene (182279). RT-PCR analysis of UBE3A for imprinted expression in cultured human fibroblasts and lymphoblasts from AS and PWS patients with large deletions using primers in exons 9 and 10 indicated biallelic expression, suggesting that UBE3A was an unlikely candidate locus for AS. </p><p>Vu and Hoffman (1997) and Rougeulle et al. (1997) showed that imprinting of the UBE3A gene is restricted to brain. Its expression is biallelic in fibroblasts, lymphoblasts, heart, kidney, and other tissues. This finding is consistent with the clinical manifestations of AS and the postmortem findings, both of which suggest that the brain is the major organ affected in this disorder. </p><p>Albrecht et al. (1997) used mice with partial paternal uniparental disomy (UPD) encompassing Ube3a to differentiate maternal and paternal expression. They found by in situ hybridization that expression of Ube3a in Purkinje cells, hippocampal neurons, and mitral cells of the olfactory bulb in UPD mice was markedly reduced compared to non-UPD littermates. In contrast, expression of Ube3a in other regions of the brain was reduced only moderately or not at all in UPD mice. The major phenotypic features of AS correlate with the loss of maternal-specific expression of Ube3a in hippocampus and cerebellum as revealed in this mouse model. </p><p>To determine possible epigenetic effects on expression within duplicated 15q11-q13 regions, Herzing et al. (2002) used RNA-FISH to observe gene expression. RNA-FISH, unlike RT-PCR, is polymorphism-independent and detects relative levels of expression at each allele. Unamplified, gene-specific RNA signals were detected using cDNA probes. Subsequent DNA-FISH confirmed RNA signals and assigned parental origin by colocalization of genomic probes. SNRPN (182279) and NDN (602117) expression was detected primarily from paternal alleles. However, maternal UBE3A signals were consistently larger than paternal signals in normal fibroblasts, neural precursor cells, on one or both maternal alleles in a cell line carrying a maternal interstitial duplication, and on both alleles of a maternally derived marker(15) chromosome. Excess total maternal UBE3A RNA was confirmed by Northern blot analysis of cell lines carrying 15q11-q13 duplications or triplications. The authors concluded that UBE3A is imprinted in fibroblasts, lymphoblasts and neural-precursor cells; that allelic imprint status is maintained in the majority of cells upon duplication both in cis and in trans; and that alleles on specific types of duplications may exhibit an increase in expression levels/loss of expression constraints. </p><p>Yamasaki et al. (2003) analyzed Ube3a imprinting status in embryonic mouse cortical cell cultures. RT-PCR and immunofluorescence were performed to determine the allelic expression of the gene. The sense transcript was expressed maternally in neurons but biallelically in glial cells in the embryonic brain, whereas the antisense transcript (UBE3AATS, or SNHG14; 616259) was expressed only in neurons and only from the paternal allele. Yamasaki et al. (2003) concluded that reciprocal imprinting of sense and antisense transcripts present only in neurons suggests a neuron-specific imprinting mechanism that is related to the lineage determination of neural stem cells. </p><p>Dindot et al. (2008) found that transgenic mice expressing fluorescence-tagged Ube3a showed expression preferentially from the maternal allele in central neurons, but biallelic expression in glial cells. Expression was detected in both neuronal cell nuclei and synapses. Mice with maternal deficiency for Ube3a had abnormal dendritic spine morphology and density on cerebellar Purkinje cells and on pyramidal neurons of the hippocampus and cortex. </p><p>Meng et al. (2013) noted that the promoters of both paternal and maternal UBE3A remain unmethylated in human brain. They found that the promoter regions of both maternal and paternal mouse Ube3a alleles were transcriptionally active. Chromatin immunoprecipitation analysis, followed by allele-specific PCR and sequencing, showed that only the transcriptionally active paternal allele of the Snrpn promoter in associated with the transcription preinitiation complex (PIC), whereas both parental alleles of the Ube3a promoter were detected in the same fraction with PIC. Strand-specific microarray data revealed a significant decrease of Ube3aats RNA around intron 4 of Ube3a, near the region where paternal Ube3a pre-mRNA becomes suppressed. Meng et al. (2013) proposed a 'transcriptional collision' model for suppression of paternal Ube3a expression, in which both Ube3a sense and antisense RNAs are transcribed head-to-head at a relatively high level until the polymerases reach intron 4, where both drop to a lower level. </p><p><strong><em>Effects of MECP2 Deficiency on UBE3A Expression</em></strong></p><p>
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Rett syndrome (312750), an X-linked dominant disorder caused by MECP2 (300005) mutations, and Angelman syndrome have phenotypic and genetic overlap with autism (209850). Samaco et al. (2005) tested the hypothesis that MECP2 deficiency may affect the level of expression of UBE3A and neighboring autism candidate gene GABRB3 (137192) without necessarily affecting imprinted expression. Multiple quantitative methods revealed significant defects in UBE3A expression in 2 different Mecp2-deficient mouse strains, as well as Rett, Angelman, and autism brain samples compared with control samples. Although no difference was observed in the allelic expression of several imprinted transcripts in Mecp2-null mouse brain, Ube3a sense expression was significantly reduced, consistent with the decrease in protein. The nonimprinted GABRB3 gene also showed significantly reduced expression in multiple Rett, Angelman, and autism brain samples, as well as Mecp2-deficient mice. Samaco et al. (2005) proposed an overlapping pathway of gene dysregulation within chromosome 15q11-q13 in Rett syndrome, Angelman syndrome, and autism, and implicated MECP2 in the regulation of UBE3A and GABRB3 expression in the postnatal mammalian brain. </p><p>Makedonski et al. (2005) showed that UBE3A mRNA and protein were significantly reduced in human and mouse MECP2-deficient brains. Reduced UBE3A level was associated with biallelic production of the UBE3A antisense RNA. In addition, MECP2 deficiency resulted in elevated histone H3 acetylation and H3(K4) methylation and reduced H3(K9) methylation at the PWS/AS imprinting center, with no effect on DNA methylation or SNRPN expression. Makedonski et al. (2005) concluded that MECP2 deficiency causes epigenetic aberrations at the PWS imprinting center. These changes in histone modifications may result in loss of imprinting of the UBE3A antisense gene in the brain, increase in UBE3A antisense RNA level and, consequently, reduction in UBE3A production. </p>
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<h4>
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<strong>Biochemical Features</strong>
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<span class="mim-text-font">
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<p>Huang et al. (1999) determined that the crystal structure of the catalytic hect domain of E6AP revealed a bilobal structure with a broad catalytic cleft at the junction of the 2 lobes. The cleft consists of conserved residues whose mutation interferes with ubiquitin-thioester bond formation and is the site of Angelman syndrome mutations. The crystal structure of E6AP hect domain bound to the UBCH7 ubiquitin-conjugating (E2) enzyme (603721) revealed the determinants of the E2-E3 specificity and provided insights into the transfer of ubiquitin from the E2 to the E3. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p>Kishino et al. (1997) found an inversion that caused Angelman syndrome (AS; 105830) when transmitted maternally and which disrupted the 5-prime end of the UBE3A gene. They subsequently identified 2 mutations in nondeletion/nonuniparental disomy/nonimprinting mutation (NDUI) AS patients that were predicted to eliminate UBE3A function. </p><p>Matsuura et al. (1997) identified 4 mutations in the UBE3A gene in AS patients, including a de novo frameshift mutation and a de novo nonsense mutation in exon 3 and 2 missense mutations of less certain significance. The de novo truncating mutations indicated that UBE3A is the AS gene and suggested the possibility of a maternally expressed gene product in addition to the biallelically expressed transcript. The authors commented that intragenic mutation of UBE3A in Angelman syndrome was the first example of a genetic disorder of the ubiquitin-dependent proteolytic pathway in mammals. It may represent an example of a human genetic disorder associated with a locus producing functionally distinct imprinted and biallelically expressed gene products. Precedent for the production of imprinted and nonimprinted transcripts from a single locus exist for insulin-like growth factor-2 (IGF2; 147470), where 4 promoters, 3 imprinted and 1 biallelically expressed, account for differential expression. </p><p>Malzac et al. (1998) identified UBE3A coding-region mutations detected by SSCP analysis in 13 AS individuals or families. In 2 cases, an identical de novo 5-bp duplication in exon 16 was found. Among the other 11 unique mutations, 8 were small deletions or insertions predicted to cause frameshifts, 1 was a mutation to a stop codon, 1 was a missense mutation, and 1 was predicted to cause insertion of an isoleucine in the hect domain of the UBE3A protein, which functions in E2 binding and ubiquitin transfer. Eight of the cases were familial, and 5 were sporadic. In 2 familial cases and 1 sporadic case, mosaicism for UBE3A mutations was detected: in the mother of 3 AS sons, in the maternal grandfather of 2 AS first cousins, and in the mother of an AS daughter. The frequency with which they detected mutations was 5 (14%) of 35 in sporadic cases and 8 (80%) of 10 in familial cases. </p><p>Fung et al. (1998) found a functionally insignificant 14-bp deletion in the 3-prime untranslated region of the UBE3A1 gene. The allelic variant was identified in the search for a mutation in a patient with what was thought to be atypical Angelman syndrome. The patient had mental retardation, lack of speech, ataxia, and a 'happy disposition.' A fair complexion, strabismus, and disrupted sleep were also observed. She was considered to be atypical since she was very short in stature and did not have a prominent mandible. In addition, her ataxia was less severe than is typically seen in Angelman syndrome, she did not exhibit inappropriate laughter, and she had normal occiput formation as well as a normal EEG at age 2 years and 6 months. The 14-bp deletion was found in the patient, her normal sib, and her unaffected mother. </p><p>Fang et al. (1999) sequenced the major coding exons of the UBE3A gene in 56 index patients with a clinical diagnosis of Angelman syndrome and a normal DNA methylation pattern. Disease-causing mutations were identified in 17 of the 56 patients (30%), including 13 truncating mutations, 2 missense mutations, 1 single amino acid deletion, and 1 stop codon mutation which predicted an elongated protein. Mutations were identified in 6 of 8 families (75%) with more than 1 affected individual, and in 11 of 47 isolated cases (23%); no mutation was found in 1 family with 2 sibs, 1 with typical and 1 with atypical phenotype. Mutations were de novo in 9 of the 11 isolated cases. An amino acid polymorphism, ala178 to thr, was identified, and a 3-bp length polymorphism was found in the intron upstream of exon 8. In all informative cases, phenotypic expression was consistent with imprinting, with a normal phenotype when the mutation was on the paternal chromosome and an Angelman syndrome phenotype when the mutation was on the maternal chromosome. </p><p>Rapakko et al. (2004) performed conformation-sensitive gel electrophoresis (CSGE) mutation analysis of the UBE3A coding region in 9 patients with Angelman syndrome who had shown a normal biparental inheritance and methylation pattern of 15q11-q13. They identified disease-causing mutations in 5 of them, including 2 missense mutations: thr106 to pro (601623.0006) and ile130 to thr (601623.0007). Two patients shared a frameshift deletion of 4 nucleotides in exon 16: 3093delAAGA (601623.0008); the fifth patient's mutation was a frameshift resulting from 1930delAG in exon 9 (601623.0009). CSGE was found to be a sensitive and simple screening method for mutations in UBE3A. </p><p>Camprubi et al. (2009) analyzed the UBE3A gene in a total of 237 AS patients with normal methylation patterns and identified 11 mutations, in 5 (13.2%) of 38 stringently selected patients and in 6 (3%) of 199 patients for whom clinical criteria were loosely applied, respectively. There was significant association between inheritance and type of mutation, with 5 single nucleotide changes being inherited from a healthy mother, whereas 4 of 5 multiple nucleotide deletions or insertions arose de novo in the patient (p = 0.02). In 1 case, an inherited mutation was present in the healthy mother, who carried the mutation in mosaic in her blood cells on the paternally derived chromosome. Review of previously published AS mutations confirmed the association with inheritance, with the proportion of multiple nucleotide deletions and insertions occurring de novo almost double that of single nucleotide substitutions (p = 0.015). Noting that only 3 of the 11 UBE3A mutations detected in this study had been previously reported, Camprubi et al. (2009) suggested that the variability of mutational changes causing AS would increase as new cases were described. </p>
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<strong>Animal Model</strong>
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<p>Jiang et al. (1998) generated transgenic mice with the maternal or paternal UBE3A genes knocked out and compared them with their wildtype (m+/p+) littermates. Mice with paternal deficiency (m+/p-) were essentially similar to wildtype mice. The phenotype of mice with maternal deficiency (m-/p+) resembles that of human AS with motor dysfunction, inducible seizures, and a context-dependent learning deficit. The absence of detectable expression of UBE3a in hippocampal neurons and Purkinje cells in m-/p+ mice, indicating imprinting with silencing of the paternal allele, correlated well with the neurologic and cognitive impairments. Long-term potentiation in the hippocampus was severely impaired. The cytoplasmic abundance of p53 was found to be greatly increased in Purkinje cells and in a subset of hippocampal neurons in m-/p+ mice, as well as in a deceased AS patient. Jiang et al. (1998) suggested that failure of Ube3a to ubiquitinate target proteins and promote their degradation could be a key aspect of the pathogenesis of AS. </p><p>Wu et al. (2008) determined that the Drosophila Dube3a gene is the counterpart of the human UBE3A gene. In normal flies, Dube3a showed ubiquitous and cytoplasmic expression in the central nervous system starting early in embryogenesis. Expression of Dube3a was enriched in the adult mushroom body, the seat of learning and memory. Dube3a-null flies appeared normal externally, but showed abnormal locomotive behavior and circadian rhythms and defective long-term memory. Mutant flies that overexpressed Dube3a in the nervous system also showed locomotion defects, as well as aberrant eye and wing morphology. The locomotion defects in flies with both null and overexpression of Dube3a were dependent on ubiquitin ligase activity. Introduction of missense UBE3A mutations into Dube3a behaved as loss-of-function mutations. Wu et al. (2008) stated that the simplest model for Angelman syndrome suggests that in the absence of UBE3A, particular substrates fail to be ubiquitinated and proteasomally degraded, accumulate in the brain, and interfere with brain function. </p><p>Greer et al. (2010) found that neurons cultured from Ube3a-knockout mice showed reduced surface expression of Glur1 at synapses compared with wildtype neurons. The effect appeared to be specific to AMPARs, since no changes were observed in the surface expression of NMDARs (see GRIN1; 138249). Whole-cell recordings of CA1 hippocampal pyramidal neurons revealed weakened AMPAR-mediated currents, but not NMDAR-mediated currents, and reduced frequency of miniature excitatory postsynaptic currents in Ube3a-knockout neurons compared with wildtype neurons. </p><p>Smith et al. (2011) stated that maternally inherited duplications and triplications in the region of chromosome 15q containing the UBE3A gene are among the most common genomic copy number variations identified in patients with autism spectrum disorder (see 608636). They developed transgenic mice with double or triple the dosage of the long form of Ube3a in neurons. Mice with 3 copies of the Ube3a gene showed defective social interaction, reduced socially elicited ultrasonic vocalization, and increased repetitive grooming behavior. Transgenic mice carrying 2 copies of Ube3a showed a more limited phenotype. Increased Ube3a gene dosage impaired excitatory synaptic transmission in layer-2/3 pyramidal neurons, with reduced presynaptic glutamate release probability and suppressed coupling of synaptic currents to firing of postsynaptic action potentials. Transgenic mice with double or triple dosage of the inactive short form of Ube3a were similar to wildtype mice in all measures. </p><p>Huang et al. (2012) used an unbiased, high-content screen in primary cortical neurons from mice, to identify 12 topoisomerase I (126420) inhibitors and 4 topoisomerase II (see 126430) inhibitors that unsilence the paternal Ube3a allele. These drugs included topotecan, irinotecan, etoposide, and dexrazoxane. At nanomolar concentrations, topotecan upregulated catalytically active UBE3A in neurons from maternal Ube3a-null mice. Topotecan concomitantly downregulated expression of the Ube3a antisense transcript that overlaps the paternal copy of Ube3a. These results indicated that topotecan unsilences Ube3a in cis by reducing transcription of an imprinted antisense RNA. When administered in vivo, topotecan unsilenced the paternal Ube3a allele in several regions of the nervous system, including neurons in the hippocampus, neocortex, striatum, cerebellum, and spinal cord. Paternal expression of Ube3a remained elevated in a subset of spinal cord neurons for at least 12 weeks after cessation of topotecan treatment, indicating that transient topoisomerase inhibition can have enduring effects on gene expression. Huang et al. (2012) concluded that, although potential off-target effects remain to be investigated, their findings suggest a therapeutic strategy for reactivating the functional but dormant allele of Ube3a in patients with Angelman syndrome. </p><p>Meng et al. (2013) observed that imprinting of UBE3A expression is not associated with differential DNA methylation at the paternal UBE3A promoter region, but is due to paternal expression of UBE3AATS. Mice heterozygous for Ube3a deletion show characteristics similar to AS, including cognitive and motor coordination defects and impaired long-term potentiation. Meng et al. (2013) found that premature termination of Ube3aats via insertion of a poly(A) cassette activated expression of Ube3a from the paternal chromosome and ameliorated many disease-related symptoms in AS mice. </p><p>By transcriptome analysis, Furumai et al. (2019) found that genes downstream of interferon regulatory factors (IRFs; see 147575) were enriched in brains of Ube3a-deficient AS mice. In vitro analysis indicated that Ube3a interacted with IRFs and promoted IRF-dependent transcriptional activities at least partially through its E3 ubiquitin ligase activity in AS mice. </p>
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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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<strong>11 Selected Examples):</strong>
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</h4>
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<span class="mim-font">
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<strong>.0001 ANGELMAN SYNDROME</strong>
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UBE3A, 5-BP DUP
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SNP: rs1555379800,
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ClinVar: RCV000193223
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<p>In a nondeletion/non-UPD/nonimprinting mutation (NDUI) Angelman syndrome (AS; 105830) patient, Kishino et al. (1997) found heterozygosity for a 5-bp de novo tandem duplication of the UBE3A gene that resulted in a frameshift and premature termination of translation. </p>
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<span class="mim-font">
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<strong>.0002 ANGELMAN SYNDROME</strong>
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UBE3A, IVS9, A-G, -8
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SNP: rs2077891986,
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|
|
|
|
ClinVar: RCV001092400, RCV001807382, RCV002402492
|
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|
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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 2 brothers with Angelman syndrome (AS; 105830), Kishino et al. (1997) found an A-to-G transition in the UBE3A gene that created a new 3-prime splice junction 7-bp upstream from the normal splice junction. The mutation was predicted to cause a frameshift and premature termination of translation. SSCP analysis of products derived with primers flanking exon 10 showed an abnormal band that was also present in their normal mother but not in their father. The normal phenotype of the mother was presumably a consequence of her having inherited the mutation from her father. </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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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 ANGELMAN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
UBE3A, 2-BP DEL, 1344GT
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<br />
|
|
|
|
SNP: rs587784512,
|
|
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|
|
|
|
|
ClinVar: RCV000147864, RCV003229812
|
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|
|
</span>
|
|
</div>
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|
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<div>
|
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<span class="mim-text-font">
|
|
<p>Matsuura et al. (1997) studied 10 patients meeting standard clinical diagnostic criteria for Angelman syndrome (AS; 105830) and 1 with possible Angelman syndrome, all having a normal methylation pattern at SNRPN (182279). One of the 11 patients was found to have a 2-bp deletion (1344delAG), resulting in a frameshift and premature termination 23 codons downstream. This mutation was not present in either parent. Fung et al. (1998) found this mutation in a patient with typical Angelman syndrome. Restriction analysis of parental amplicons with XbaI and EcoRI demonstrated that the allele was not carried by either parent. Nonpaternity was excluded on the basis of genotyping with 5 highly polymorphic markers. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 ANGELMAN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
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UBE3A, ARG417TER
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<br />
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|
|
SNP: rs111033594,
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|
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gnomAD: rs111033594,
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|
|
ClinVar: RCV000008430
|
|
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|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Angelman syndrome (AS; 105830), Matsuura et al. (1997) identified an arg417-to-ter (R417X) nonsense mutation. This mutation resulted in loss of a TaqI restriction enzyme site. An analysis of the family revealed that this was a de novo mutation. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
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|
</div>
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|
|
</div>
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|
|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 ANGELMAN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
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|
|
|
UBE3A, TRP768TER
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<br />
|
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|
|
SNP: rs111033595,
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|
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|
|
ClinVar: RCV000008431
|
|
|
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|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family of mixed Ashkenazi and Iraqi Jewish descent, Tsai et al. (1998) observed 2 children affected with Angelman syndrome (AS; 105830). Sequence analysis for the 10 major coding exons of UBE3A identified a nonsense mutation in exon 15. The mutation was a G-to-A substitution at nucleotide 2304, which caused a nonsense mutation (trp768 to ter) at the protein level. The mother was heterozygous for the mutation. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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|
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|
|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 ANGELMAN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
UBE3A, THR106PRO
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<br />
|
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|
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SNP: rs111033596,
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|
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|
|
|
ClinVar: RCV000008432
|
|
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|
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</span>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Angelman syndrome (AS; 105830) who had shown a normal biparental inheritance and methylation pattern of 15q11-q13, Rapakko et al. (2004) identified a 902A-C transversion in exon 9 of the UBE3A gene, resulting in a thr106-to-pro amino acid substitution (T106P). The patient's mother was mosaic for the mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 ANGELMAN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
UBE3A, ILE130THR
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs111033597,
|
|
|
|
|
|
|
|
ClinVar: RCV000008433
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Angelman syndrome (AS; 105830) who had shown a normal biparental inheritance and methylation pattern of 15q11-q13, Rapakko et al. (2004) identified a 975T-C transition in exon 9 of the UBE3A gene, resulting in an ile130-to-thr amino acid substitution (I130T). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 ANGELMAN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
UBE3A, 4-BP DEL, 3093AAGA
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000147883, RCV000481125, RCV000622970, RCV001260843
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 patients with Angelman syndrome (AS; 105830) who had shown a normal biparental inheritance and methylation pattern of 15q11-q13, Rapakko et al. (2004) identified a 4-bp deletion in exon 16 of the UBE3A gene, 3093delAAGA, that resulted in a frameshift and premature termination. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 ANGELMAN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
UBE3A, 2-BP DEL, 1930AG
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000147864, RCV003229812
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Angelman syndrome (AS; 105830) who had shown a normal biparental inheritance and methylation pattern of 15q11-q13, Rapakko et al. (2004) identified a 2-bp deletion in exon 9 of the UBE3A gene, 1930delAG, that resulted in a frameshift and premature termination. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 ANGELMAN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
UBE3A, 4-BP DUP, EX10, GAGG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2152505917,
|
|
|
|
|
|
|
|
ClinVar: RCV000008436
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 first cousins with Angelman syndrome (AS; 105830), Molfetta et al. (2003) identified a duplication of GAGG in exon 10 of the UBE3A gene, which caused a frameshift and premature termination. The mutation was inherited from their asymptomatic mothers. Molfetta et al. (2004) reported that these first cousins presented discordant phenotypes. The proband had typical AS features, whereas her cousin had a more severe phenotype with asymmetric spasticity, which originally led to the diagnosis of cerebral palsy, and severe brain malformations on MRI. Because the cousins' grandfather had transmitted the mutation to only 2 of 8 sibs, Molfetta et al. (2004) raised the hypothesis of mosaicism for this mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 ANGELMAN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
UBE3A, 15-BP DEL/7-BP INS, NT3240
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000023125
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of large highly consanguineous Tunisian kindred with Angelman syndrome (AS; 105830), Abaied et al. (2010) identified a heterozygous complex mutation involving the UBE3A gene: a 15-bp deletion and 7-bp insertion (3240_3255delinsAGATGTT) at the same position in exon 16, resulting in a frameshift, premature termination, and likely a nonfunctional protein. There were 14 affected individuals, who were all in the same generation, and all patients inherited the mutation from their carrier mothers, who were 4 sisters. These 4 sisters apparently inherited the mutation from their unaffected father, who was deceased. All patients had a severe form of Angelman syndrome, with mental retardation, motor impairment, seizures, hyperactivity, and frequent laughing. Two had severe microcephaly, which Abaied et al. (2010) postulated could be due to a different homozygous mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Abaied, L., Trabelsi, M., Chaabouni, M., Kharrat, M., Kraoua, L., M'rad, R., Tebib, N., Maazoul, F., Chaabouni, H.
|
|
<strong>A novel UBE3A truncating mutation in large Tunisian Angelman syndrome pedigree.</strong>
|
|
Am. J. Med. Genet. 152A: 141-146, 2010.
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|
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|
|
[PubMed: 20034088]
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|
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|
|
[Full Text: https://doi.org/10.1002/ajmg.a.33179]
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Albrecht, U., Sutcliffe, J. S., Cattanach, B. M., Beechey, C. V., Armstrong, D., Eichele, G., Beaudet, A. L.
|
|
<strong>Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons.</strong>
|
|
Nature Genet. 17: 75-78, 1997.
|
|
|
|
|
|
[PubMed: 9288101]
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|
|
[Full Text: https://doi.org/10.1038/ng0997-75]
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|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Camprubi, C., Guitart, M., Gabau, E., Coll, M. D., Villatoro, S., Oltra, S., Rosello, M., Ferrer, I., Monfort, S., Orellana, C., Martinez, F.
|
|
<strong>Novel UBE3A mutations causing Angelman syndrome: different parental origin for single nucleotide changes and multiple nucleotide deletions or insertions.</strong>
|
|
Am. J. Med. Genet. 149A: 343-348, 2009.
|
|
|
|
|
|
[PubMed: 19213023]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.32659]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Dindot, S. V., Antalffy, B. A., Bhattacharjee, M. B., Beaudet, A. L.
|
|
<strong>The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology.</strong>
|
|
Hum. Molec. Genet. 17: 111-118, 2008.
|
|
|
|
|
|
[PubMed: 17940072]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddm288]
|
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|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Fang, N. N., Ng, A. H. M., Measday, V., Mayor, T.
|
|
<strong>Hul5 HECT ubiquitin ligase plays a major role in the ubiquitylation and turnover of cytosolic misfolded proteins.</strong>
|
|
Nature Cell Biol. 13: 1344-1352, 2011.
|
|
|
|
|
|
[PubMed: 21983566]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ncb2343]
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Fang, P., Lev-Lehman, E., Tsai, T.-F., Matsuura, T., Benton, C. S., Sutcliffe, J. S., Christian, S. L., Kubota, T., Halley, D. J., Meijers-Heijboer, H., Langlois, S., Graham, J. M., Jr., Beuten, J., Willems, P. J., Ledbetter, D. H., Beaudet, A. L.
|
|
<strong>The spectrum of mutations in UBE3A causing Angelman syndrome.</strong>
|
|
Hum. Molec. Genet. 8: 129-135, 1999.
|
|
|
|
|
|
[PubMed: 9887341]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/8.1.129]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Fung, D. C. Y., Yu, B., Cheong, K. F., Smith, A., Trent, R. J.
|
|
<strong>UBE3A 'mutations' in two unrelated and phenotypically different Angelman syndrome patients.</strong>
|
|
Hum. Genet. 102: 487-492, 1998.
|
|
|
|
|
|
[PubMed: 9600250]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s004390050727]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Furumai, R., Tamada, K., Liu, X., Takumi, T.
|
|
<strong>UBE3A regulates the transcription of IRF, an antiviral immunity.</strong>
|
|
Hum. Molec. Genet. 28: 1947-1958, 2019.
|
|
|
|
|
|
[PubMed: 30690483]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddz019]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Greer, P. L., Hanayama, R., Bloodgood, B. L., Mardinly, A. R., Lipton, D. M., Flavell, S. W., Kim, T.-K., Griffith, E. C., Waldon, Z., Maehr, R., Ploegh, H. L., Chowdhury, S., Worley, P. F., Steen, J., Greenberg, M. E.
|
|
<strong>The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating Arc.</strong>
|
|
Cell 140: 704-716, 2010.
|
|
|
|
|
|
[PubMed: 20211139]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.cell.2010.01.026]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Herzing, L. B. K., Cook, E. H., Ledbetter, D. H.
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Ada Hamosh - updated : 05/07/2020<br>Bao Lige - updated : 02/18/2020<br>Ada Hamosh - updated : 03/15/2018<br>Patricia A. Hartz - updated : 3/10/2015<br>Patricia A. Hartz - updated : 1/14/2014<br>Patricia A. Hartz - updated : 11/26/2013<br>Ada Hamosh - updated : 2/7/2012<br>Patricia A. Hartz - updated : 2/25/2011<br>Cassandra L. Kniffin - updated : 1/6/2011<br>Patricia A. Hartz - updated : 12/14/2010<br>Marla J. F. O'Neill - updated : 8/27/2010<br>Patricia A. Hartz - updated : 9/21/2009<br>George E. Tiller - updated : 7/31/2009<br>Cassandra L. Kniffin - updated : 5/28/2009<br>Matthew B. Gross - reorganized : 4/10/2009<br>Patricia A. Hartz - updated : 4/10/2009<br>George E. Tiller - updated : 2/7/2008<br>George E. Tiller - updated : 1/3/2008<br>George E. Tiller - updated : 2/21/2005<br>Carol A. Bocchini - updated : 11/3/2004<br>Victor A. McKusick - updated : 4/14/2004<br>George E. Tiller - updated : 6/18/2003<br>Wilson H. Y. Lo - updated : 4/7/2000<br>Ada Hamosh - updated : 11/11/1999<br>Victor A. McKusick - updated : 2/17/1999<br>Victor A. McKusick - updated : 12/8/1998<br>Clair A. Francomano - updated : 6/26/1998<br>Victor A. McKusick - updated : 6/23/1998<br>Rebekah S. Rasooly - updated : 5/19/1998<br>Victor A. McKusick - updated : 8/28/1997
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Victor A. McKusick : 1/10/1997
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