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Entry
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- *612024 - OTU DOMAIN-CONTAINING PROTEIN 7A; OTUD7A
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- OMIM
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<p>
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<span class="h4">*612024</span>
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<br />
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<strong>Table of Contents</strong>
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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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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/612024">Table View</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<h4 class="panel-title">
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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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<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=ENSG00000169918;t=ENST00000307050" 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=161725" 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=612024" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000169918;t=ENST00000307050" 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_001329907,NM_001382637,NM_130901" 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_001382637" 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=612024" 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 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=12666&isoform_id=12666_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/OTUD7A" 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/18644082,18702331,27370636,45126296,51701344,119581673,119581674,119581675,119581676,119581677,608785543,1049480179,1843014501" 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/Q8TE49" 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=161725" 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=ENSG00000169918;t=ENST00000307050" 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=OTUD7A" 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=OTUD7A" 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+161725" 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/OTUD7A" 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:161725" 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/161725" 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=ENST00000307050.6&hgg_start=31475398&hgg_end=31870673&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:20718" 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:20718" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=612024[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 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=612024[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000169918" 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=OTUD7A" 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=OTUD7A" 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=OTUD7A" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=OTUD7A&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/PA134877572" 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:20718" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:2158505" 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/OTUD7A#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:2158505" 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/161725/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=161725" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00021733;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-100212-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=OTUD7A&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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612024
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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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OTU DOMAIN-CONTAINING PROTEIN 7A; OTUD7A
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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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OTUD7<br />
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CHROMOSOME 16 OPEN READING FRAME 15; C16ORF15<br />
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CEZANNE2
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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=OTUD7A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">OTUD7A</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/15/57?start=-3&limit=10&highlight=57">15q13.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:31475398-31870673&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'})">15:31,475,398-31,870,673</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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<a href="/geneMap/15/57?start=-3&limit=10&highlight=57">
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15q13.3
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Neurodevelopmental disorder with hypotonia and seizures
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/620790"> 620790 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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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/612024" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/612024" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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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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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
|
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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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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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<p>The OTUD7A gene encodes a member of a family of deubiquitinating enzymes (DUBs; see <a href="/entry/603478">603478</a>), which are proteases that specifically cleave ubiquitin (<a href="/entry/191339">191339</a>) linkages from proteins targeted for degradation. OTUD7A also localizes to the postsynaptic density in the brain, suggesting a role in synapse development and maturation (summary by <a href="#7" class="mim-tip-reference" title="Uddin, M., Unda, B. K., Kwan, V., Holzapfel, N. T., White, S. H., Chalil, L., Woodbury-Smith, M., Ho, K. S., Harward, E., Murtaza, N., Dave, B., Pellecchia, G., and 12 others. <strong>OTUD7A regulates neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome.</strong> Am. J. Hum. Genet. 102: 278-295, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29395074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29395074</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29395074[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.01.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29395074">Uddin et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29395074" 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>OTUD7A belongs to a DUB subfamily characterized by an ovarian tumor (OTU) domain (<a href="#4" class="mim-tip-reference" title="Kayagaki, N., Phung, Q., Chan, S., Chaudhari, R., Quan, C., O'Rourke, K. M., Eby, M., Pietras, E., Cheng, G., Bazan, J. F., Zhang, Z., Arnott, D., Dixit, V. M. <strong>DUBA: a deubiquitinase that regulates type I interferon production.</strong> Science 318: 1628-1632, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17991829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17991829</a>] [<a href="https://doi.org/10.1126/science.1145918" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17991829">Kayagaki et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17991829" 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="#4" class="mim-tip-reference" title="Kayagaki, N., Phung, Q., Chan, S., Chaudhari, R., Quan, C., O'Rourke, K. M., Eby, M., Pietras, E., Cheng, G., Bazan, J. F., Zhang, Z., Arnott, D., Dixit, V. M. <strong>DUBA: a deubiquitinase that regulates type I interferon production.</strong> Science 318: 1628-1632, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17991829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17991829</a>] [<a href="https://doi.org/10.1126/science.1145918" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17991829">Kayagaki et al. (2007)</a> identified ovarian tumor domain (OTU)-containing protein 7A (OTUD7A) in a small interfering RNA (siRNA)-based screen for OTU deubiquitinating enzyme (DUB) family members. The 3,042-basepair mRNA contains an open reading frame (ORF) predicting a 926-amino acid protein. In addition to an OTU domain, the protein contains an A20-like zinc finger (ZNF A20) domain at the carboxy terminus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17991829" 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="Uddin, M., Unda, B. K., Kwan, V., Holzapfel, N. T., White, S. H., Chalil, L., Woodbury-Smith, M., Ho, K. S., Harward, E., Murtaza, N., Dave, B., Pellecchia, G., and 12 others. <strong>OTUD7A regulates neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome.</strong> Am. J. Hum. Genet. 102: 278-295, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29395074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29395074</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29395074[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.01.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29395074">Uddin et al. (2018)</a> found highest expression of the OTUD7A gene in human brain tissue compared to other human tissues. Network analysis suggested that the OTUD7A gene plays an important role in a brain-specific protein module and is likely involved in brain-specific synaptic signaling. Otud7a was also identified in the developing mouse brain during early postnatal stages when dendrites and dendritic spines are forming. Gene expression was localized to neuronal soma and dendrites in a punctate pattern, and also showed localization to the postsynaptic region of excitatory synapses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29395074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the mouse brain, <a href="#8" class="mim-tip-reference" title="Yin, J., Chen, W., Chao, E. S., Soriano, S., Wang, L., Wang, W., Cummock, S. E., Tao, H., Pang, K., Liu, Z., Pereira, F. A., Samaco, R. C., Zoghbi, H. Y., Xue, M., Schaaf, C. P. <strong>Otud7a knockout mice recapitulate many neurological features of 15q13.3 microdeletion syndrome.</strong> Am. J. Hum. Genet. 102: 296-308, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29395075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29395075</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29395075[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.01.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29395075">Yin et al. (2018)</a> found high expression of Otud7a in primary cortical neurons with enrichment at dendritic spines and membrane compartments in the cell body. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29395075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The OTUD7A gene maps to chromosome 15q13.3 (<a href="#4" class="mim-tip-reference" title="Kayagaki, N., Phung, Q., Chan, S., Chaudhari, R., Quan, C., O'Rourke, K. M., Eby, M., Pietras, E., Cheng, G., Bazan, J. F., Zhang, Z., Arnott, D., Dixit, V. M. <strong>DUBA: a deubiquitinase that regulates type I interferon production.</strong> Science 318: 1628-1632, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17991829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17991829</a>] [<a href="https://doi.org/10.1126/science.1145918" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17991829">Kayagaki et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17991829" 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="#2" class="mim-tip-reference" title="Garret, P., Ebstein, F., Delplancq, G., Dozieres-Puyravel, B., Boughalem, A., Auvin, S., Duffourd, Y., Klafack, S., Zieba, B. A., Mahmoudi, S., Singh, K. K., Duplomb, L., Thauvin-Robinet, C., Costa, J.-M., Kruger, E., Trost, D., Verloes, A., Faivre, L., Vitobello, A. <strong>Report of the first patient with a homozygous OTUD7A variant responsible for epileptic encephalopathy and related proteasome dysfunction.</strong> Clin. Genet. 97: 567-575, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31997314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31997314</a>] [<a href="https://doi.org/10.1111/cge.13709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31997314">Garret et al. (2020)</a> demonstrated that OTUD7A plays a role in proteasome function by regulating the steady-state expression level of the P28 proteosome regulator and its alpha (PSME1; <a href="/entry/600654">600654</a>) and beta (PSME2; <a href="/entry/602161">602161</a>) subunits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31997314" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#7" class="mim-tip-reference" title="Uddin, M., Unda, B. K., Kwan, V., Holzapfel, N. T., White, S. H., Chalil, L., Woodbury-Smith, M., Ho, K. S., Harward, E., Murtaza, N., Dave, B., Pellecchia, G., and 12 others. <strong>OTUD7A regulates neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome.</strong> Am. J. Hum. Genet. 102: 278-295, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29395074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29395074</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29395074[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.01.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29395074">Uddin et al. (2018)</a> performed whole-genome or whole-exome sequencing in over 6,000 individuals with a neurodevelopmental disorder who did not have a 15q13.3 microdeletion (see the 15q13.3 deletion syndrome, <a href="/entry/612001">612001</a>) and detected 8 de novo mutations in genes within the breakpoint interval (BP4-BP5), 3 of which occurred in the OTUD7A gene. In 2 sibs (proband is case 3) with autism spectrum disorder (ASD), <a href="#7" class="mim-tip-reference" title="Uddin, M., Unda, B. K., Kwan, V., Holzapfel, N. T., White, S. H., Chalil, L., Woodbury-Smith, M., Ho, K. S., Harward, E., Murtaza, N., Dave, B., Pellecchia, G., and 12 others. <strong>OTUD7A regulates neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome.</strong> Am. J. Hum. Genet. 102: 278-295, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29395074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29395074</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29395074[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.01.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29395074">Uddin et al. (2018)</a> identified a de novo heterozygous 9-bp in-frame deletion in the OTUD7A gene (asn492_lys494del). In vitro studies showed that the mutation resulted in normal levels of mutant protein production, but that mutant protein was not able to rescue the abnormal dendritic phenotype of mouse neurons with heterozygous deletion of chromosome 15q13 (Df(h15q13)+/- mouse mutants; see ANIMAL MODEL). Expression of mutant OTUD7A in cultured wildtype neurons significantly reduced dendritic spine length, consistent with a mild dominant-negative effect. Studies of patient cells were not performed. <a href="#7" class="mim-tip-reference" title="Uddin, M., Unda, B. K., Kwan, V., Holzapfel, N. T., White, S. H., Chalil, L., Woodbury-Smith, M., Ho, K. S., Harward, E., Murtaza, N., Dave, B., Pellecchia, G., and 12 others. <strong>OTUD7A regulates neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome.</strong> Am. J. Hum. Genet. 102: 278-295, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29395074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29395074</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29395074[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.01.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29395074">Uddin et al. (2018)</a> also identified 2 additional unrelated patients with ASD associated with de novo heterozygous intronic variants in the OTUD7A gene (c.-223+11014A-G and c.1150+935del); functional studies of these variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29395074" 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="Kozlova, A., Zhang, S., Kotlar, A. V., Jamison, B., Zhang, H., Shi, S., Forrest, M. P., McDaid, J., Cutler, D. J., Epstein, M. P., Zwick, M. E., Pang, Z. P., Sanders, A. R., Warren, S. T., Gejman, P. V., Mulle, J. G., Duan, J. <strong>Loss of function of OTUD7A in the schizophrenia- associated 15q13.3 deletion impairs synapse development and function in human neurons.</strong> Am. J. Hum. Genet. 109: 1500-1519, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35931052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35931052</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35931052[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2022.07.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35931052">Kozlova et al. (2022)</a> performed targeted sequencing of genes within schizophrenia-associated copy-number variants (CNVs) in 1,779 schizophrenia cases and 1,418 controls. They identified 3 patients with rare variants in the OTUD7A gene, which is located within the chromosome 15q13.3 deletion interval that is associated with a variety of neuropsychiatric phenotypes. None of the variants reached statistical significance. The rare variants included arg89 to ter (R89X, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs757148409;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs757148409</a>), glu136 to ter (E136X), and asn492_lys494del (c.1474_1482del). The asn492_lys494del variant had been identified by <a href="#7" class="mim-tip-reference" title="Uddin, M., Unda, B. K., Kwan, V., Holzapfel, N. T., White, S. H., Chalil, L., Woodbury-Smith, M., Ho, K. S., Harward, E., Murtaza, N., Dave, B., Pellecchia, G., and 12 others. <strong>OTUD7A regulates neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome.</strong> Am. J. Hum. Genet. 102: 278-295, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29395074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29395074</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29395074[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.01.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29395074">Uddin et al. (2018)</a> in 2 sibs with autism. <a href="#5" class="mim-tip-reference" title="Kozlova, A., Zhang, S., Kotlar, A. V., Jamison, B., Zhang, H., Shi, S., Forrest, M. P., McDaid, J., Cutler, D. J., Epstein, M. P., Zwick, M. E., Pang, Z. P., Sanders, A. R., Warren, S. T., Gejman, P. V., Mulle, J. G., Duan, J. <strong>Loss of function of OTUD7A in the schizophrenia- associated 15q13.3 deletion impairs synapse development and function in human neurons.</strong> Am. J. Hum. Genet. 109: 1500-1519, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35931052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35931052</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35931052[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2022.07.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35931052">Kozlova et al. (2022)</a> modeled the OTUD7A variant R89X in human induced pluripotent stem cell (hiPSC)-derived induced excitatory neurons (iNs) by CRISPR-Cas9 engineering. The mutant iNs showed an approximately 50% decrease in OTUD7A protein expression without undergoing nonsense-mediated mRNA decay. The mutant iNs also exhibited marked reduction of dendritic complexity, density of synaptic proteins GluA1 (<a href="/entry/138248">138248</a>) and PSD95 (<a href="/entry/602887">602887</a>), and neuronal network activity. Congruent with the neuronal phenotypes in mutant iNs, transcriptomic analysis showed that the set of genes downregulated by OTUD7A loss of function was enriched for those relating to synapse development and function and was associated with schizophrenia and other neuropsychiatric disorders. <a href="#3" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 9/14/2022."None>Hamosh (2022)</a> found that, in gnomAD, the asn492_lys494del variant had the highest minor allele frequency in South Asians (0.0001001, 3/29,964 alleles), but was also seen in 1 African American and 3 non-Finnish Europeans. <a href="#3" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 9/14/2022."None>Hamosh (2022)</a> found the R89X variant (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs757148409;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs757148409</a>) in 1 Finnish and 1 non-Finnish European in gnomAD, for an allele frequency of 0.0000080. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=35931052+29395074" 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>Neurodevelopmental Disorder With Hypotonia And Seizures</em></strong></p><p>
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In a 28-month-old boy, born of distantly consanguineous Portuguese parents, with neurodevelopmental disorder with hypotonia and seizures (NEDHS; <a href="/entry/620790">620790</a>), <a href="#2" class="mim-tip-reference" title="Garret, P., Ebstein, F., Delplancq, G., Dozieres-Puyravel, B., Boughalem, A., Auvin, S., Duffourd, Y., Klafack, S., Zieba, B. A., Mahmoudi, S., Singh, K. K., Duplomb, L., Thauvin-Robinet, C., Costa, J.-M., Kruger, E., Trost, D., Verloes, A., Faivre, L., Vitobello, A. <strong>Report of the first patient with a homozygous OTUD7A variant responsible for epileptic encephalopathy and related proteasome dysfunction.</strong> Clin. Genet. 97: 567-575, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31997314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31997314</a>] [<a href="https://doi.org/10.1111/cge.13709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31997314">Garret et al. (2020)</a> identified a homozygous missense mutation in the OTUD7A gene (L233F; <a href="#0001">612024.0001</a>). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each parent, both of whom had learning disabilities. The variant was not present in the gnomAD database. Patient fibroblasts showed decreased enzymatic activity of the 20S proteasome complex compared to controls. Although levels of the 20S and 26S proteosomes were normal, there were decreased amounts of the PA28 (see PA28A, <a href="/entry/600654">600654</a>)-20S and free PA28 complexes, as well as decreased levels of certain PA28 and 20S proteasome subunits. Similar findings were observed in OTUD7A-null HAP1 cells. The reduced proteasome activity was associated with accumulation of insoluble proteins modified with K48-linked ubiquitin chains targeted for proteasome-mediated degradation, indicating disrupted protein homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31997314" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 3-year-old boy with NEDHS, <a href="#6" class="mim-tip-reference" title="Suzuki, H., Inaba, M., Yamada, M., Uehara, T., Takenouchi, T., Mizuno, S., Kosaki, K., Doi, M. <strong>Biallelic loss of OTUD7A causes severe muscular hypotonia, intellectual disability, and seizures.</strong> Am. J. Med. Genet. 185A: 1182-1186, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33381903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33381903</a>] [<a href="https://doi.org/10.1002/ajmg.a.62054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33381903">Suzuki et al. (2021)</a> identified compound heterozygous loss of the OTUD7A gene. He had a de novo heterozygous frameshift mutation (<a href="#0002">612024.0002</a>) and a de novo heterozygous 1.6-Mb microdeletion of chromosome 15q13.3, which included the OTUD7A gene (see <a href="/entry/612001">612001</a>). The point mutation was found by trio-based exome sequencing and confirmed by Sanger sequencing, whereas the deletion was identified through copy number variant analysis. Neither parent carried the mutation or the deletion. Studies of patient cells were not performed, but homozygous expression of the frameshift mutation in the C. elegans homolog resulted in impaired locomotion and disturbed synaptic transmission (see ANIMAL MODEL). The authors concluded that the frameshift mutation is a loss-of-function allele and that the motor defects could have resulted from reduced synaptic transmission from motor neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33381903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Fejgin, K., Nielsen, J., Birknow, M. R., Bastlund, J. F., Nielsen, V., Lauridsen, J. B., Stefansson, H., Steinberg, S., Sorensen, H. B. D., Mortensen, T. E., Larsen, P. H., Klewe, I. V., Rasmussen, S. V., Stefansson, K., Werge, T. M., Kallunki, P., Christensen, K. V., Didriksen, M. <strong>A mouse model that recapitulates cardinal features of the 15q13.3 microdeletion syndrome including schizophrenia- and epilepsy-related alterations.</strong> Biol. Psychiat. 76: 128-137, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24090792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24090792</a>] [<a href="https://doi.org/10.1016/j.biopsych.2013.08.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24090792">Fejgin et al. (2014)</a> found that mutant mice with a heterozygous 15q13.3 microdeletion (Df(h15q13)/+) showed marked changes in neuronal excitability in acute seizure assays, with increased propensity to develop myoclonic and absence-like seizures, but decreased propensity for clonic and tonic seizures. Mutant mice had impaired long-term spatial reference memory and a decreased theta frequency in the hippocampus and prefrontal cortex, as well as auditory processing deficits similar to those observed in schizophrenia. The neurologic abnormalities in these mice recapitulated some of the phenotypic features observed in humans with 15q13.3 deletions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24090792" 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 RNA sequencing, <a href="#7" class="mim-tip-reference" title="Uddin, M., Unda, B. K., Kwan, V., Holzapfel, N. T., White, S. H., Chalil, L., Woodbury-Smith, M., Ho, K. S., Harward, E., Murtaza, N., Dave, B., Pellecchia, G., and 12 others. <strong>OTUD7A regulates neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome.</strong> Am. J. Hum. Genet. 102: 278-295, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29395074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29395074</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29395074[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.01.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29395074">Uddin et al. (2018)</a> found that Df(h15q13)/+ mice had significantly decreased expression of several genes involved in forebrain cortical development, including Chrna7 (<a href="/entry/118511">118511</a>) and Otud7a. This decreased expression was associated with a small, but significant, reduction in dendritic spine density, mature mushroom-shaped spines, dendritic length, and dendritic arborization in the frontal cortex compared to wildtype. Isolated cortical neurons from heterozygous mutant mice showed similar abnormalities. Expression of wildtype OTUD7A was able to rescue the abnormalities in dendritic spine density, length, and the proportion of mushroom and stubby spines, but expression of CHRNA7, KLF13 (<a href="/entry/605328">605328</a>), or FAN1 (<a href="/entry/613534">613534</a>), other genes within the candidate region, was unable to rescue these defects. However, CHRNA7 was able to rescue dendrite outgrowth, suggesting some potential overlap in function. <a href="#7" class="mim-tip-reference" title="Uddin, M., Unda, B. K., Kwan, V., Holzapfel, N. T., White, S. H., Chalil, L., Woodbury-Smith, M., Ho, K. S., Harward, E., Murtaza, N., Dave, B., Pellecchia, G., and 12 others. <strong>OTUD7A regulates neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome.</strong> Am. J. Hum. Genet. 102: 278-295, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29395074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29395074</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29395074[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.01.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29395074">Uddin et al. (2018)</a> concluded that OTUD7A is a critical gene in the 15q13.3 microdeletion syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29395074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Yin, J., Chen, W., Chao, E. S., Soriano, S., Wang, L., Wang, W., Cummock, S. E., Tao, H., Pang, K., Liu, Z., Pereira, F. A., Samaco, R. C., Zoghbi, H. Y., Xue, M., Schaaf, C. P. <strong>Otud7a knockout mice recapitulate many neurological features of 15q13.3 microdeletion syndrome.</strong> Am. J. Hum. Genet. 102: 296-308, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29395075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29395075</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29395075[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.01.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29395075">Yin et al. (2018)</a> found that homozygous Otud7a-null mice had preweaning growth delay and delayed motor milestones, increased seizure-like activity, and impaired vocalization, although memory and learning appeared to be normal as measured by fear conditioning and novel object recognition tests. Homozygous and heterozygous-null mice showed impaired acoustic startle response compared to wildtype, and female mutant mice had reduced prepulse inhibition, all of which may represent features of schizophrenia. Primary cortical neurons derived from Otud7a-null mice showed a significant reduction in dendritic spine density compared to controls, and this defect could be rescued by expression of wildtype Otud7a, although there were no apparent defects in dendritic growth or dendritic complexity. Primary neurons from mutant mice also showed a decrease in functioning excitatory synapses. <a href="#8" class="mim-tip-reference" title="Yin, J., Chen, W., Chao, E. S., Soriano, S., Wang, L., Wang, W., Cummock, S. E., Tao, H., Pang, K., Liu, Z., Pereira, F. A., Samaco, R. C., Zoghbi, H. Y., Xue, M., Schaaf, C. P. <strong>Otud7a knockout mice recapitulate many neurological features of 15q13.3 microdeletion syndrome.</strong> Am. J. Hum. Genet. 102: 296-308, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29395075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29395075</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29395075[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.01.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29395075">Yin et al. (2018)</a> concluded that OTUD7A deficiency largely accounts for the human phenotypes associated with 15q13.3 deletion syndrome and that OTUD7A is important in the regulation of dendritic spine density and activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29395075" 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>The OTUD7A homolog in C. elegans is otub2, which is expressed in the nervous system. <a href="#6" class="mim-tip-reference" title="Suzuki, H., Inaba, M., Yamada, M., Uehara, T., Takenouchi, T., Mizuno, S., Kosaki, K., Doi, M. <strong>Biallelic loss of OTUD7A causes severe muscular hypotonia, intellectual disability, and seizures.</strong> Am. J. Med. Genet. 185A: 1182-1186, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33381903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33381903</a>] [<a href="https://doi.org/10.1002/ajmg.a.62054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33381903">Suzuki et al. (2021)</a> found that C. elegans carrying a homozygous CRISPR/Cas9-generated mutation in the otub2 gene that corresponded to a frameshift mutation identified in a human patient (<a href="#0002">612024.0002</a>) developed normally, but had impaired locomotion with disturbed movement patterns and smaller movement amplitudes compared to wildtype. This abnormality was not observed in heterozygous mutant worms. The authors concluded that the frameshift mutation is a loss-of-function allele and that the motor defects could have resulted from reduced synaptic transmission from motor neurons to body wall muscles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33381903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 28-month-old boy, born of distantly consanguineous Portuguese parents, with neurodevelopmental disorder with hypotonia and seizures (NEDHS; <a href="/entry/620790">620790</a>), <a href="#2" class="mim-tip-reference" title="Garret, P., Ebstein, F., Delplancq, G., Dozieres-Puyravel, B., Boughalem, A., Auvin, S., Duffourd, Y., Klafack, S., Zieba, B. A., Mahmoudi, S., Singh, K. K., Duplomb, L., Thauvin-Robinet, C., Costa, J.-M., Kruger, E., Trost, D., Verloes, A., Faivre, L., Vitobello, A. <strong>Report of the first patient with a homozygous OTUD7A variant responsible for epileptic encephalopathy and related proteasome dysfunction.</strong> Clin. Genet. 97: 567-575, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31997314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31997314</a>] [<a href="https://doi.org/10.1111/cge.13709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31997314">Garret et al. (2020)</a> identified a homozygous c.697C-T transition (c.697C-T, NM_130901.2) in the OTUD7A gene, resulting in a leu233-to-phe (L233F) substitution at a highly conserved residue in the OTU catalytic domain. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each parent, both of whom had learning disabilities. The variant was not present in the gnomAD database. Of note, the patient also carried a maternally inherited hemizygous missense variant (T553A) in the ACSL4 gene (<a href="/entry/300157">300157</a>) that may have contributed to the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31997314" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA AND SEIZURES</strong>
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OTUD7A, 1-BP DEL, NT1125
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV004525824" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004525824" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004525824</a>
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<p>In a 3-year-old boy, born of unrelated parents, with neurodevelopmental disorder with hypotonia and seizures (NEDHS; <a href="/entry/620790">620790</a>), <a href="#6" class="mim-tip-reference" title="Suzuki, H., Inaba, M., Yamada, M., Uehara, T., Takenouchi, T., Mizuno, S., Kosaki, K., Doi, M. <strong>Biallelic loss of OTUD7A causes severe muscular hypotonia, intellectual disability, and seizures.</strong> Am. J. Med. Genet. 185A: 1182-1186, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33381903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33381903</a>] [<a href="https://doi.org/10.1002/ajmg.a.62054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33381903">Suzuki et al. (2021)</a> identified compound heterozygosity for loss of the OTUD7A gene. He had a de novo heterozygous 1-bp deletion (c.1125del, NM_130901.2) in the OTUD7A gene, resulting in a frameshift and premature termination (Glu375AspfsTer11) on 1 allele, and a de novo heterozygous 1.6-Mb deletion of chromosome 15q13.3 (see <a href="/entry/612001">612001</a>) that included the OTUD7A gene on the other allele. The point mutation was found by trio-based exome sequencing and confirmed by Sanger sequencing, whereas the deletion was identified through copy number variant analysis. Neither parent carried the mutation or the deletion. Functional studies of the variants and studies of patient cells were not performed, but homozygous expression of the frameshift mutation in the C. elegans homolog resulted in impaired locomotion and disturbed synaptic transmission (see ANIMAL MODEL). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33381903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="Fejgin2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Fejgin, K., Nielsen, J., Birknow, M. R., Bastlund, J. F., Nielsen, V., Lauridsen, J. B., Stefansson, H., Steinberg, S., Sorensen, H. B. D., Mortensen, T. E., Larsen, P. H., Klewe, I. V., Rasmussen, S. V., Stefansson, K., Werge, T. M., Kallunki, P., Christensen, K. V., Didriksen, M.
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<strong>A mouse model that recapitulates cardinal features of the 15q13.3 microdeletion syndrome including schizophrenia- and epilepsy-related alterations.</strong>
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Biol. Psychiat. 76: 128-137, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24090792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24090792</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24090792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.biopsych.2013.08.014" target="_blank">Full Text</a>]
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<a id="Garret2020" class="mim-anchor"></a>
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Garret, P., Ebstein, F., Delplancq, G., Dozieres-Puyravel, B., Boughalem, A., Auvin, S., Duffourd, Y., Klafack, S., Zieba, B. A., Mahmoudi, S., Singh, K. K., Duplomb, L., Thauvin-Robinet, C., Costa, J.-M., Kruger, E., Trost, D., Verloes, A., Faivre, L., Vitobello, A.
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<strong>Report of the first patient with a homozygous OTUD7A variant responsible for epileptic encephalopathy and related proteasome dysfunction.</strong>
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Clin. Genet. 97: 567-575, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31997314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31997314</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31997314" 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/10.1111/cge.13709" target="_blank">Full Text</a>]
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<a id="Hamosh2022" class="mim-anchor"></a>
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Hamosh, A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 9/14/2022.
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Kayagaki, N., Phung, Q., Chan, S., Chaudhari, R., Quan, C., O'Rourke, K. M., Eby, M., Pietras, E., Cheng, G., Bazan, J. F., Zhang, Z., Arnott, D., Dixit, V. M.
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<strong>DUBA: a deubiquitinase that regulates type I interferon production.</strong>
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Science 318: 1628-1632, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17991829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17991829</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17991829" 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/10.1126/science.1145918" target="_blank">Full Text</a>]
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<a id="Kozlova2022" class="mim-anchor"></a>
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Kozlova, A., Zhang, S., Kotlar, A. V., Jamison, B., Zhang, H., Shi, S., Forrest, M. P., McDaid, J., Cutler, D. J., Epstein, M. P., Zwick, M. E., Pang, Z. P., Sanders, A. R., Warren, S. T., Gejman, P. V., Mulle, J. G., Duan, J.
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<strong>Loss of function of OTUD7A in the schizophrenia- associated 15q13.3 deletion impairs synapse development and function in human neurons.</strong>
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Am. J. Hum. Genet. 109: 1500-1519, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35931052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35931052</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35931052[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=35931052" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2022.07.001" target="_blank">Full Text</a>]
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Suzuki, H., Inaba, M., Yamada, M., Uehara, T., Takenouchi, T., Mizuno, S., Kosaki, K., Doi, M.
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<strong>Biallelic loss of OTUD7A causes severe muscular hypotonia, intellectual disability, and seizures.</strong>
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Am. J. Med. Genet. 185A: 1182-1186, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33381903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33381903</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33381903" 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.62054" target="_blank">Full Text</a>]
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Uddin, M., Unda, B. K., Kwan, V., Holzapfel, N. T., White, S. H., Chalil, L., Woodbury-Smith, M., Ho, K. S., Harward, E., Murtaza, N., Dave, B., Pellecchia, G., and 12 others.
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<strong>OTUD7A regulates neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome.</strong>
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Am. J. Hum. Genet. 102: 278-295, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29395074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29395074</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29395074[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=29395074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2018.01.006" target="_blank">Full Text</a>]
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Yin, J., Chen, W., Chao, E. S., Soriano, S., Wang, L., Wang, W., Cummock, S. E., Tao, H., Pang, K., Liu, Z., Pereira, F. A., Samaco, R. C., Zoghbi, H. Y., Xue, M., Schaaf, C. P.
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<strong>Otud7a knockout mice recapitulate many neurological features of 15q13.3 microdeletion syndrome.</strong>
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Am. J. Hum. Genet. 102: 296-308, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29395075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29395075</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29395075[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=29395075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2018.01.005" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 04/24/2024
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Ada Hamosh - updated : 09/14/2022<br>Cassandra L. Kniffin - updated : 03/23/2018
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Ada Hamosh : 5/6/2008
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ckniffin : 04/24/2024<br>alopez : 09/14/2022<br>carol : 07/23/2018<br>alopez : 03/28/2018<br>ckniffin : 03/23/2018<br>alopez : 05/07/2008<br>alopez : 5/6/2008
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<strong>*</strong> 612024
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OTU DOMAIN-CONTAINING PROTEIN 7A; OTUD7A
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OTUD7<br />
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CHROMOSOME 16 OPEN READING FRAME 15; C16ORF15<br />
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CEZANNE2
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Cytogenetic location: 15q13.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 15:31,475,398-31,870,673 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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15q13.3
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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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Neurodevelopmental disorder with hypotonia and seizures
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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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620790
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The OTUD7A gene encodes a member of a family of deubiquitinating enzymes (DUBs; see 603478), which are proteases that specifically cleave ubiquitin (191339) linkages from proteins targeted for degradation. OTUD7A also localizes to the postsynaptic density in the brain, suggesting a role in synapse development and maturation (summary by Uddin et al., 2018). </p><p>OTUD7A belongs to a DUB subfamily characterized by an ovarian tumor (OTU) domain (Kayagaki et al., 2007). </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>Kayagaki et al. (2007) identified ovarian tumor domain (OTU)-containing protein 7A (OTUD7A) in a small interfering RNA (siRNA)-based screen for OTU deubiquitinating enzyme (DUB) family members. The 3,042-basepair mRNA contains an open reading frame (ORF) predicting a 926-amino acid protein. In addition to an OTU domain, the protein contains an A20-like zinc finger (ZNF A20) domain at the carboxy terminus. </p><p>Uddin et al. (2018) found highest expression of the OTUD7A gene in human brain tissue compared to other human tissues. Network analysis suggested that the OTUD7A gene plays an important role in a brain-specific protein module and is likely involved in brain-specific synaptic signaling. Otud7a was also identified in the developing mouse brain during early postnatal stages when dendrites and dendritic spines are forming. Gene expression was localized to neuronal soma and dendrites in a punctate pattern, and also showed localization to the postsynaptic region of excitatory synapses. </p><p>In the mouse brain, Yin et al. (2018) found high expression of Otud7a in primary cortical neurons with enrichment at dendritic spines and membrane compartments in the cell body. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The OTUD7A gene maps to chromosome 15q13.3 (Kayagaki et al., 2007). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Garret et al. (2020) demonstrated that OTUD7A plays a role in proteasome function by regulating the steady-state expression level of the P28 proteosome regulator and its alpha (PSME1; 600654) and beta (PSME2; 602161) subunits. </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>Molecular Genetics</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Uddin et al. (2018) performed whole-genome or whole-exome sequencing in over 6,000 individuals with a neurodevelopmental disorder who did not have a 15q13.3 microdeletion (see the 15q13.3 deletion syndrome, 612001) and detected 8 de novo mutations in genes within the breakpoint interval (BP4-BP5), 3 of which occurred in the OTUD7A gene. In 2 sibs (proband is case 3) with autism spectrum disorder (ASD), Uddin et al. (2018) identified a de novo heterozygous 9-bp in-frame deletion in the OTUD7A gene (asn492_lys494del). In vitro studies showed that the mutation resulted in normal levels of mutant protein production, but that mutant protein was not able to rescue the abnormal dendritic phenotype of mouse neurons with heterozygous deletion of chromosome 15q13 (Df(h15q13)+/- mouse mutants; see ANIMAL MODEL). Expression of mutant OTUD7A in cultured wildtype neurons significantly reduced dendritic spine length, consistent with a mild dominant-negative effect. Studies of patient cells were not performed. Uddin et al. (2018) also identified 2 additional unrelated patients with ASD associated with de novo heterozygous intronic variants in the OTUD7A gene (c.-223+11014A-G and c.1150+935del); functional studies of these variants and studies of patient cells were not performed. </p><p>Kozlova et al. (2022) performed targeted sequencing of genes within schizophrenia-associated copy-number variants (CNVs) in 1,779 schizophrenia cases and 1,418 controls. They identified 3 patients with rare variants in the OTUD7A gene, which is located within the chromosome 15q13.3 deletion interval that is associated with a variety of neuropsychiatric phenotypes. None of the variants reached statistical significance. The rare variants included arg89 to ter (R89X, rs757148409), glu136 to ter (E136X), and asn492_lys494del (c.1474_1482del). The asn492_lys494del variant had been identified by Uddin et al. (2018) in 2 sibs with autism. Kozlova et al. (2022) modeled the OTUD7A variant R89X in human induced pluripotent stem cell (hiPSC)-derived induced excitatory neurons (iNs) by CRISPR-Cas9 engineering. The mutant iNs showed an approximately 50% decrease in OTUD7A protein expression without undergoing nonsense-mediated mRNA decay. The mutant iNs also exhibited marked reduction of dendritic complexity, density of synaptic proteins GluA1 (138248) and PSD95 (602887), and neuronal network activity. Congruent with the neuronal phenotypes in mutant iNs, transcriptomic analysis showed that the set of genes downregulated by OTUD7A loss of function was enriched for those relating to synapse development and function and was associated with schizophrenia and other neuropsychiatric disorders. Hamosh (2022) found that, in gnomAD, the asn492_lys494del variant had the highest minor allele frequency in South Asians (0.0001001, 3/29,964 alleles), but was also seen in 1 African American and 3 non-Finnish Europeans. Hamosh (2022) found the R89X variant (rs757148409) in 1 Finnish and 1 non-Finnish European in gnomAD, for an allele frequency of 0.0000080. </p><p><strong><em>Neurodevelopmental Disorder With Hypotonia And Seizures</em></strong></p><p>
|
|
In a 28-month-old boy, born of distantly consanguineous Portuguese parents, with neurodevelopmental disorder with hypotonia and seizures (NEDHS; 620790), Garret et al. (2020) identified a homozygous missense mutation in the OTUD7A gene (L233F; 612024.0001). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each parent, both of whom had learning disabilities. The variant was not present in the gnomAD database. Patient fibroblasts showed decreased enzymatic activity of the 20S proteasome complex compared to controls. Although levels of the 20S and 26S proteosomes were normal, there were decreased amounts of the PA28 (see PA28A, 600654)-20S and free PA28 complexes, as well as decreased levels of certain PA28 and 20S proteasome subunits. Similar findings were observed in OTUD7A-null HAP1 cells. The reduced proteasome activity was associated with accumulation of insoluble proteins modified with K48-linked ubiquitin chains targeted for proteasome-mediated degradation, indicating disrupted protein homeostasis. </p><p>In a 3-year-old boy with NEDHS, Suzuki et al. (2021) identified compound heterozygous loss of the OTUD7A gene. He had a de novo heterozygous frameshift mutation (612024.0002) and a de novo heterozygous 1.6-Mb microdeletion of chromosome 15q13.3, which included the OTUD7A gene (see 612001). The point mutation was found by trio-based exome sequencing and confirmed by Sanger sequencing, whereas the deletion was identified through copy number variant analysis. Neither parent carried the mutation or the deletion. Studies of patient cells were not performed, but homozygous expression of the frameshift mutation in the C. elegans homolog resulted in impaired locomotion and disturbed synaptic transmission (see ANIMAL MODEL). The authors concluded that the frameshift mutation is a loss-of-function allele and that the motor defects could have resulted from reduced synaptic transmission from motor neurons. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
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|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Fejgin et al. (2014) found that mutant mice with a heterozygous 15q13.3 microdeletion (Df(h15q13)/+) showed marked changes in neuronal excitability in acute seizure assays, with increased propensity to develop myoclonic and absence-like seizures, but decreased propensity for clonic and tonic seizures. Mutant mice had impaired long-term spatial reference memory and a decreased theta frequency in the hippocampus and prefrontal cortex, as well as auditory processing deficits similar to those observed in schizophrenia. The neurologic abnormalities in these mice recapitulated some of the phenotypic features observed in humans with 15q13.3 deletions. </p><p>Using RNA sequencing, Uddin et al. (2018) found that Df(h15q13)/+ mice had significantly decreased expression of several genes involved in forebrain cortical development, including Chrna7 (118511) and Otud7a. This decreased expression was associated with a small, but significant, reduction in dendritic spine density, mature mushroom-shaped spines, dendritic length, and dendritic arborization in the frontal cortex compared to wildtype. Isolated cortical neurons from heterozygous mutant mice showed similar abnormalities. Expression of wildtype OTUD7A was able to rescue the abnormalities in dendritic spine density, length, and the proportion of mushroom and stubby spines, but expression of CHRNA7, KLF13 (605328), or FAN1 (613534), other genes within the candidate region, was unable to rescue these defects. However, CHRNA7 was able to rescue dendrite outgrowth, suggesting some potential overlap in function. Uddin et al. (2018) concluded that OTUD7A is a critical gene in the 15q13.3 microdeletion syndrome. </p><p>Yin et al. (2018) found that homozygous Otud7a-null mice had preweaning growth delay and delayed motor milestones, increased seizure-like activity, and impaired vocalization, although memory and learning appeared to be normal as measured by fear conditioning and novel object recognition tests. Homozygous and heterozygous-null mice showed impaired acoustic startle response compared to wildtype, and female mutant mice had reduced prepulse inhibition, all of which may represent features of schizophrenia. Primary cortical neurons derived from Otud7a-null mice showed a significant reduction in dendritic spine density compared to controls, and this defect could be rescued by expression of wildtype Otud7a, although there were no apparent defects in dendritic growth or dendritic complexity. Primary neurons from mutant mice also showed a decrease in functioning excitatory synapses. Yin et al. (2018) concluded that OTUD7A deficiency largely accounts for the human phenotypes associated with 15q13.3 deletion syndrome and that OTUD7A is important in the regulation of dendritic spine density and activity. </p><p>The OTUD7A homolog in C. elegans is otub2, which is expressed in the nervous system. Suzuki et al. (2021) found that C. elegans carrying a homozygous CRISPR/Cas9-generated mutation in the otub2 gene that corresponded to a frameshift mutation identified in a human patient (612024.0002) developed normally, but had impaired locomotion with disturbed movement patterns and smaller movement amplitudes compared to wildtype. This abnormality was not observed in heterozygous mutant worms. The authors concluded that the frameshift mutation is a loss-of-function allele and that the motor defects could have resulted from reduced synaptic transmission from motor neurons to body wall muscles. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
|
|
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</div>
|
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|
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|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>2 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA AND SEIZURES</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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|
|
OTUD7A, LEU233PHE
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|
|
<br />
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|
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SNP: rs1162953058,
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|
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ClinVar: RCV001263452, RCV001263453, RCV004526099
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 28-month-old boy, born of distantly consanguineous Portuguese parents, with neurodevelopmental disorder with hypotonia and seizures (NEDHS; 620790), Garret et al. (2020) identified a homozygous c.697C-T transition (c.697C-T, NM_130901.2) in the OTUD7A gene, resulting in a leu233-to-phe (L233F) substitution at a highly conserved residue in the OTU catalytic domain. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each parent, both of whom had learning disabilities. The variant was not present in the gnomAD database. Of note, the patient also carried a maternally inherited hemizygous missense variant (T553A) in the ACSL4 gene (300157) that may have contributed to the phenotype. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA AND SEIZURES</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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OTUD7A, 1-BP DEL, NT1125
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<br />
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ClinVar: RCV004525824
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-year-old boy, born of unrelated parents, with neurodevelopmental disorder with hypotonia and seizures (NEDHS; 620790), Suzuki et al. (2021) identified compound heterozygosity for loss of the OTUD7A gene. He had a de novo heterozygous 1-bp deletion (c.1125del, NM_130901.2) in the OTUD7A gene, resulting in a frameshift and premature termination (Glu375AspfsTer11) on 1 allele, and a de novo heterozygous 1.6-Mb deletion of chromosome 15q13.3 (see 612001) that included the OTUD7A gene on the other allele. The point mutation was found by trio-based exome sequencing and confirmed by Sanger sequencing, whereas the deletion was identified through copy number variant analysis. Neither parent carried the mutation or the deletion. Functional studies of the variants and studies of patient cells were not performed, but homozygous expression of the frameshift mutation in the C. elegans homolog resulted in impaired locomotion and disturbed synaptic transmission (see ANIMAL MODEL). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
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</h4>
|
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<div>
|
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<p />
|
|
</div>
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<div>
|
|
<ol>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Fejgin, K., Nielsen, J., Birknow, M. R., Bastlund, J. F., Nielsen, V., Lauridsen, J. B., Stefansson, H., Steinberg, S., Sorensen, H. B. D., Mortensen, T. E., Larsen, P. H., Klewe, I. V., Rasmussen, S. V., Stefansson, K., Werge, T. M., Kallunki, P., Christensen, K. V., Didriksen, M.
|
|
<strong>A mouse model that recapitulates cardinal features of the 15q13.3 microdeletion syndrome including schizophrenia- and epilepsy-related alterations.</strong>
|
|
Biol. Psychiat. 76: 128-137, 2014.
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[PubMed: 24090792]
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[Full Text: https://doi.org/10.1016/j.biopsych.2013.08.014]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
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Garret, P., Ebstein, F., Delplancq, G., Dozieres-Puyravel, B., Boughalem, A., Auvin, S., Duffourd, Y., Klafack, S., Zieba, B. A., Mahmoudi, S., Singh, K. K., Duplomb, L., Thauvin-Robinet, C., Costa, J.-M., Kruger, E., Trost, D., Verloes, A., Faivre, L., Vitobello, A.
|
|
<strong>Report of the first patient with a homozygous OTUD7A variant responsible for epileptic encephalopathy and related proteasome dysfunction.</strong>
|
|
Clin. Genet. 97: 567-575, 2020.
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[PubMed: 31997314]
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[Full Text: https://doi.org/10.1111/cge.13709]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Hamosh, A.
|
|
<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 9/14/2022.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kayagaki, N., Phung, Q., Chan, S., Chaudhari, R., Quan, C., O'Rourke, K. M., Eby, M., Pietras, E., Cheng, G., Bazan, J. F., Zhang, Z., Arnott, D., Dixit, V. M.
|
|
<strong>DUBA: a deubiquitinase that regulates type I interferon production.</strong>
|
|
Science 318: 1628-1632, 2007.
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[PubMed: 17991829]
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[Full Text: https://doi.org/10.1126/science.1145918]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kozlova, A., Zhang, S., Kotlar, A. V., Jamison, B., Zhang, H., Shi, S., Forrest, M. P., McDaid, J., Cutler, D. J., Epstein, M. P., Zwick, M. E., Pang, Z. P., Sanders, A. R., Warren, S. T., Gejman, P. V., Mulle, J. G., Duan, J.
|
|
<strong>Loss of function of OTUD7A in the schizophrenia- associated 15q13.3 deletion impairs synapse development and function in human neurons.</strong>
|
|
Am. J. Hum. Genet. 109: 1500-1519, 2022.
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|
[PubMed: 35931052]
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[Full Text: https://doi.org/10.1016/j.ajhg.2022.07.001]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Suzuki, H., Inaba, M., Yamada, M., Uehara, T., Takenouchi, T., Mizuno, S., Kosaki, K., Doi, M.
|
|
<strong>Biallelic loss of OTUD7A causes severe muscular hypotonia, intellectual disability, and seizures.</strong>
|
|
Am. J. Med. Genet. 185A: 1182-1186, 2021.
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[PubMed: 33381903]
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[Full Text: https://doi.org/10.1002/ajmg.a.62054]
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</p>
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</li>
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<li>
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Uddin, M., Unda, B. K., Kwan, V., Holzapfel, N. T., White, S. H., Chalil, L., Woodbury-Smith, M., Ho, K. S., Harward, E., Murtaza, N., Dave, B., Pellecchia, G., and 12 others.
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<strong>OTUD7A regulates neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome.</strong>
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Am. J. Hum. Genet. 102: 278-295, 2018.
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[PubMed: 29395074]
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[Full Text: https://doi.org/10.1016/j.ajhg.2018.01.006]
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Yin, J., Chen, W., Chao, E. S., Soriano, S., Wang, L., Wang, W., Cummock, S. E., Tao, H., Pang, K., Liu, Z., Pereira, F. A., Samaco, R. C., Zoghbi, H. Y., Xue, M., Schaaf, C. P.
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<strong>Otud7a knockout mice recapitulate many neurological features of 15q13.3 microdeletion syndrome.</strong>
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Am. J. Hum. Genet. 102: 296-308, 2018.
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[PubMed: 29395075]
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[Full Text: https://doi.org/10.1016/j.ajhg.2018.01.005]
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Cassandra L. Kniffin - updated : 04/24/2024<br>Ada Hamosh - updated : 09/14/2022<br>Cassandra L. Kniffin - updated : 03/23/2018
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Ada Hamosh : 5/6/2008
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alopez : 04/25/2024<br>ckniffin : 04/24/2024<br>alopez : 09/14/2022<br>carol : 07/23/2018<br>alopez : 03/28/2018<br>ckniffin : 03/23/2018<br>alopez : 05/07/2008<br>alopez : 5/6/2008
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