3983 lines
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Entry
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- *602887 - DISCS LARGE MAGUK SCAFFOLD PROTEIN 4; DLG4
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- OMIM
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<p>
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<span class="h4">*602887</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</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/602887">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000132535;t=ENST00000399506" 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=1742" 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=602887" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000132535;t=ENST00000399506" 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_001128827,NM_001321074,NM_001321075,NM_001321076,NM_001321077,NM_001365,NM_001369566,NR_135527" 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_001321075" 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=602887" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=04199&isoform_id=04199_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/DLG4" 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/1527215,2613006,3318653,4557529,5918874,71658825,73909118,119610657,119610658,119610659,119610660,119610661,192447426,221039688,221041302,221041762,221042912,221045580,223460510,1007359288,1007359549,1007359556,1007359809,1612259794" 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/P78352" 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=1742" 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=ENSG00000132535;t=ENST00000399506" 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=DLG4" 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=DLG4" 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+1742" 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/DLG4" 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:1742" 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/1742" 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=chr17&hgg_gene=ENST00000399506.9&hgg_start=7187187&hgg_end=7220050&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:2903" 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:2903" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/dlg4" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=602887[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=602887[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/DLG4/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000132535" 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=DLG4" 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=DLG4" 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=DLG4" 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=DLG4&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/PA27359" 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:2903" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0001624.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1277959" 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/DLG4#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:1277959" 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/1742/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=1742" 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=WBGene00001006;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-040628-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:602887" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:1742" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=DLG4&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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602887
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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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DISCS LARGE MAGUK SCAFFOLD PROTEIN 4; DLG4
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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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DISCS LARGE, DROSOPHILA, HOMOLOG OF, 4<br />
|
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POSTSYNAPTIC DENSITY 95; PSD95<br />
|
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SYNAPSE-ASSOCIATED PROTEIN 90; SAP90
|
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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=DLG4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">DLG4</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
|
Cytogenetic location: <a href="/geneMap/17/138?start=-3&limit=10&highlight=138">17p13.1</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr17:7187187-7220050&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'})">17:7,187,187-7,220,050</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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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>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
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</tr>
|
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</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/17/138?start=-3&limit=10&highlight=138">
|
|
17p13.1
|
|
</a>
|
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</span>
|
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</td>
|
|
|
|
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|
<td>
|
|
<span class="mim-font">
|
|
Intellectual developmental disorder, autosomal dominant 62
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/618793"> 618793 </a>
|
|
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
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</span>
|
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</td>
|
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<td>
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<p>DLG4 belongs to the discs large (DLG) subfamily of the membrane-associated guanylate kinase (MAGUK) family (see DLG1; <a href="/entry/601014">601014</a>). DLG4 interacts with both N-methyl-D-aspartate (NMDA) receptors (see <a href="/entry/138249">138249</a>) and Shaker-type potassium channels (see <a href="/entry/176260">176260</a>) and plays an important role in the formation and maintenance of synaptic junctions (<a href="#27" class="mim-tip-reference" title="Zhou, C., Blumberg, B. <strong>Overlapping gene structure of human VLCAD and DLG4.</strong> Gene 305: 161-166, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12609736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12609736</a>] [<a href="https://doi.org/10.1016/s0378-1119(02)01235-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12609736">Zhou and Blumberg, 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12609736" 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>Proteins related to Drosophila 'discs large' (Dlg) are associated with the cortical actin cytoskeleton and appear to have both structural and functional roles. By screening a human mammary gland cDNA library with a human EST showing homology to rat Psd95, which is also known as Sap90 (<a href="#16" class="mim-tip-reference" title="Kistner, U., Wenzel, B. M., Veh, R. W., Cases-Langhoff, C., Garner, A. M., Appeltauer, U., Voss, B., Gundelfinger, E. D., Garner, C. C. <strong>SAP90, a rat presynaptic protein related to the product of the Drosophila tumor suppressor gene, dLg-A.</strong> J. Biol. Chem. 268: 4580-4583, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7680343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7680343</a>]" pmid="7680343">Kistner et al., 1993</a>), <a href="#22" class="mim-tip-reference" title="Stathakis, D. G., Hoover, K. B., You, Z., Bryant, P. J. <strong>Human postsynaptic density-95 (PSD95): location of the gene (DLG4) and possible function in nonneural as well as in neural tissues.</strong> Genomics 44: 71-82, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9286702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9286702</a>] [<a href="https://doi.org/10.1006/geno.1997.4848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9286702">Stathakis et al. (1997)</a> cloned a cDNA encoding DLG4, which they called PSD95. The predicted 723-amino acid DLG4 protein has 3 PSD95-DLG-Z01 (PDZ) domains in its N-terminal half, a central src homology-3 (SH3) motif, and a C-terminal guanylate kinase (GUK)-homologous domain. The human DLG4 protein is 99% identical to the rat and mouse Psd95 proteins and 56% identical to the Drosophila Dlg protein. Northern blot analysis detected 6 DLG4 transcripts with different expression patterns, including a 4.2-kb transcript that was variably expressed in all 17 human tissues examined. Western blot analysis using antibodies against DLG4 detected multiple proteins with complex distribution patterns, including a ubiquitous 85-kD and tissue-specific variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7680343+9286702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By examining human brain, mammary gland, pancreas, and testis cDNA libraries, <a href="#23" class="mim-tip-reference" title="Stathakis, D. G., Udar, N., Sandgren, O., Andreasson, S., Bryant, P. J., Small, K., Forsman-Semb, K. <strong>Genomic organization of human DLG4, the gene encoding postsynaptic density 95.</strong> J. Neurochem. 73: 2250-2265, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10582582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10582582</a>] [<a href="https://doi.org/10.1046/j.1471-4159.1999.0732250.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10582582">Stathakis et al. (1999)</a> identified 3 splice variants of DLG4. A transcript lacking exon 3 was detected in brain, but not in other tissues. This variant introduces an early frameshift and encodes a predicted 45-amino acid peptide. However, a downstream ORF from exons 4 through 22 has the potential to encode a 664-amino acid protein containing all functional domains of DLG4, with a single residue before the first PDZ domain. A variant lacking exon 20 was detected in mammary gland and testis, but not in brain or pancreas. This variant encodes a deduced 670-amino acid protein that lacks part of the C-terminal GUK domain. A variant containing a 99-nucleotide extension of exon 4 (exon 4b) was detected in testis, but not in other tissues. This variant encodes a deduced 803-amino acid protein with 33 additional amino acids inserted before the first PDZ domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10582582" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Zhou, C., Blumberg, B. <strong>Overlapping gene structure of human VLCAD and DLG4.</strong> Gene 305: 161-166, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12609736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12609736</a>] [<a href="https://doi.org/10.1016/s0378-1119(02)01235-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12609736">Zhou and Blumberg (2003)</a> stated that the N terminus of DLG4 is modified by thioester-linked palmitate, which targets the protein to cell membranes. Palmitoylation is also a critical regulatory mechanism for receptor interactions with DLG4. Real-time RT-PCR detected DLG4 expression in all tissues examined, with highest expression in brain, followed by heart, placenta, lung, pancreas, spleen, thymus, testis, ovary, and small intestine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12609736" 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 proper distribution of voltage-gated and ligand-gated ion channels on the neuronal surface is critical for the processing and transmission of electrical signals in neurons. <a href="#14" class="mim-tip-reference" title="Kim, E., Niethammer, M., Rothschild, A., Jan, Y. N., Sheng, M. <strong>Clustering of Shaker-type K+ channels by interaction with a family of membrane-associated guanylate kinases.</strong> Nature 378: 85-88, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7477295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7477295</a>] [<a href="https://doi.org/10.1038/378085a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7477295">Kim et al. (1995)</a> and <a href="#13" class="mim-tip-reference" title="Kim, E., Cho, K.-O., Rothschild, A., Sheng, M. <strong>Heteromultimerization and NMDA receptor-clustering activity of Chapsyn-110, a member of the PSD-95 family of proteins.</strong> Neuron 17: 103-113, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8755482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8755482</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80284-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8755482">Kim et al. (1996)</a> demonstrated that PSD95 and chapsyn-110 (<a href="/entry/603583">603583</a>) mediated clustering of both NMDA receptors and potassium channels. Chapsyn-110 and PSD95 heteromultimerized with each other and were recruited into the same NMDA receptor and potassium channel clusters. <a href="#13" class="mim-tip-reference" title="Kim, E., Cho, K.-O., Rothschild, A., Sheng, M. <strong>Heteromultimerization and NMDA receptor-clustering activity of Chapsyn-110, a member of the PSD-95 family of proteins.</strong> Neuron 17: 103-113, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8755482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8755482</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80284-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8755482">Kim et al. (1996)</a> suggested that these 2 proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7477295+8755482" 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 cultured cortical neurons, <a href="#21" class="mim-tip-reference" title="Sattler, R., Xiong, Z., Lu, W.-Y., Hafner, M., MacDonald, J. F., Tymianski, M. <strong>Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein.</strong> Science 284: 1845-1848, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10364559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10364559</a>] [<a href="https://doi.org/10.1126/science.284.5421.1845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10364559">Sattler et al. (1999)</a> suppressed expression of the NMDA receptor scaffolding protein PSD95 and observed selective attenuation of excitotoxicity triggered via NMDA receptors, but not by other glutamate or calcium ion channels. NMDA receptor function was unaffected because receptor expression, NMDA currents, and calcium-45 loading were unchanged. Suppressing PSD95 blocked calcium-activated nitric oxide production by NMDA receptors selectively without affecting neuronal nitric oxide synthase expression or function. Thus, PSD95 is required for efficient coupling of NMDAR activity to nitric oxide toxicity and imparts specificity to excitotoxic calcium signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10364559" 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="El-Husseini, A. E.-D., Schnell, E., Chetkovich, D. M., Nicoll, R. A., Bredt, D. S. <strong>PSD-95 involvement in maturation of excitatory synapses.</strong> Science 290: 1364-1368, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11082065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11082065</a>]" pmid="11082065">El-Husseini et al. (2000)</a> found that overexpression of PSD95 in hippocampal neurons could drive maturation of glutamatergic synapses. PSD95 expression enhanced postsynaptic clustering and activity of glutamate receptors. Postsynaptic expression of PSD95 also enhanced maturation of the presynaptic terminal. These effects required synaptic clustering of PSD95 but did not rely on its guanylate kinase domain. PSD95 expression also increased the number and size of dendritic spines. <a href="#8" class="mim-tip-reference" title="El-Husseini, A. E.-D., Schnell, E., Chetkovich, D. M., Nicoll, R. A., Bredt, D. S. <strong>PSD-95 involvement in maturation of excitatory synapses.</strong> Science 290: 1364-1368, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11082065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11082065</a>]" pmid="11082065">El-Husseini et al. (2000)</a> concluded that PSD95 can orchestrate synaptic development and suggested that PSD95 has a role in synapse stabilization and plasticity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11082065" 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>Neuregulins and their receptors, the ERBB protein tyrosine kinases, are essential for neuronal development, but their functions in the adult central nervous system are unknown. <a href="#12" class="mim-tip-reference" title="Huang, Y. Z., Won, S., Ali, D. W., Wang, Q., Tanowitz, M., Du, Q. S., Pelkey, K. A., Yang, D. J., Xiong, W. C., Salter, M. W., Mei, L. <strong>Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses.</strong> Neuron 26: 443-455, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839362</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)81176-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839362">Huang et al. (2000)</a> reported that ERBB4 (<a href="/entry/600543">600543</a>) is enriched in the postsynaptic density and associates with PSD95. Heterologous expression of PSD95 enhanced NRG (<a href="/entry/142445">142445</a>) activation of ERBB4 and MAP kinase (see <a href="/entry/176948">176948</a>). Conversely, inhibiting expression of PSD95 in neurons attenuated NRG-mediated activation of MAP kinase. PSD95 formed a ternary complex with 2 molecules of ERBB4, suggesting that PSD95 facilitates ERBB4 dimerization. Finally, NRG suppressed induction of long-term potentiation in the hippocampal CA1 region without affecting basal synaptic transmission. Thus, NRG signaling may be synaptic and regulated by PSD95. <a href="#12" class="mim-tip-reference" title="Huang, Y. Z., Won, S., Ali, D. W., Wang, Q., Tanowitz, M., Du, Q. S., Pelkey, K. A., Yang, D. J., Xiong, W. C., Salter, M. W., Mei, L. <strong>Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses.</strong> Neuron 26: 443-455, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839362</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)81176-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839362">Huang et al. (2000)</a> concluded that a role of NRG signaling in the adult central nervous system may be modulation of synaptic plasticity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10839362" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Garcia, R. A. G., Vasudevan, K., Buonanno, A. <strong>The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses.</strong> Proc. Nat. Acad. Sci. 97: 3596-3601, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10725395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10725395</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10725395[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.97.7.3596" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10725395">Garcia et al. (2000)</a> found that Erbb4 and Psd95 coimmunoprecipitated from rat forebrain lysates and that the direct interaction was mediated through the C-terminal end of Erbb4. Immunofluorescent studies of cultured rat hippocampal cells showed that Erbb4 colocalized with Psd95 and NMDA receptors at interneuronal postsynaptic sites. The findings suggested that certain ERBB receptors interact with other receptors and may be important in activity-dependent synaptic plasticity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10725395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="El-Husseini, A. E.-D., Schnell, E., Dakoji, S., Sweeney, N., Zhou, Q., Prange, O., Gauthier-Campbell, C., Aguilera-Moreno, A., Nicoll, R. A., Bredt, D. S. <strong>Synaptic strength regulated by palmitate cycling on PSD-95.</strong> Cell 108: 849-863, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11955437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11955437</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00683-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11955437">El-Husseini et al. (2002)</a> identified palmitate cycling on PSD95 at the synapse and found that palmitate turnover on PSD95 is regulated by glutamate receptor activity. Acutely blocking palmitoylation dispersed synaptic clusters of PSD95 and caused a selective loss of synaptic AMPA receptors (e.g., GRIA1; <a href="/entry/138248">138248</a>). The authors also found that rapid glutamate-mediated AMPA receptor internalization requires depalmitoylation of PSD95. In a nonneuronal model system, clustering of PSD95, stargazin (<a href="/entry/602911">602911</a>), and AMPA receptors was also regulated by ongoing palmitoylation of PSD95 at the plasma membrane. <a href="#9" class="mim-tip-reference" title="El-Husseini, A. E.-D., Schnell, E., Dakoji, S., Sweeney, N., Zhou, Q., Prange, O., Gauthier-Campbell, C., Aguilera-Moreno, A., Nicoll, R. A., Bredt, D. S. <strong>Synaptic strength regulated by palmitate cycling on PSD-95.</strong> Cell 108: 849-863, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11955437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11955437</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00683-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11955437">El-Husseini et al. (2002)</a> concluded that palmitate cycling on PSD95 can regulate synaptic strength and activity-dependent plasticity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11955437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To treat stroke without blocking NMDA receptors, <a href="#1" class="mim-tip-reference" title="Aarts, M., Liu, Y., Liu, L., Besshoh, S., Arundine, M., Gurd, J. W., Wang, Y.-T., Salter, M. W., Tymianski, M. <strong>Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions.</strong> Science 298: 846-850, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12399596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12399596</a>] [<a href="https://doi.org/10.1126/science.1072873" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12399596">Aarts et al. (2002)</a> transduced neurons with peptides that disrupted the interaction of NMDA receptors with the postsynaptic density protein PSD95. This procedure dissociated NMDA receptors from downstream neurotoxic signaling without blocking synaptic activity or calcium influx. The peptides, when applied either before or 1 hour after an insult, protected cultured neurons from excitotoxicity, reduced focal ischemic brain damage in rats, and improved their neurologic function. <a href="#1" class="mim-tip-reference" title="Aarts, M., Liu, Y., Liu, L., Besshoh, S., Arundine, M., Gurd, J. W., Wang, Y.-T., Salter, M. W., Tymianski, M. <strong>Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions.</strong> Science 298: 846-850, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12399596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12399596</a>] [<a href="https://doi.org/10.1126/science.1072873" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12399596">Aarts et al. (2002)</a> concluded that their approach circumvents the negative consequences associated with blocking NMDA receptors and may constitute a practical stroke therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12399596" 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 cotransfection experiments, <a href="#24" class="mim-tip-reference" title="Tanemoto, M., Fujita, A., Higashi, K., Kurachi, Y. <strong>PSD-95 mediates formation of a functional homomeric Kir5.1 channel in the brain.</strong> Neuron 34: 387-397, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11988170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11988170</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00675-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11988170">Tanemoto et al. (2002)</a> showed that Kir5.1 (KCNJ16; <a href="/entry/605722">605722</a>) assembled to form a functional homomeric potassium channel by interacting with PSD95. The authors observed that Kir5.1 expressed alone was distributed mostly in the cytoplasm, but Kir5.1 coexpressed with PSD95 was located on the plasma membrane in a clustered manner. Using GST pull-down studies, <a href="#24" class="mim-tip-reference" title="Tanemoto, M., Fujita, A., Higashi, K., Kurachi, Y. <strong>PSD-95 mediates formation of a functional homomeric Kir5.1 channel in the brain.</strong> Neuron 34: 387-397, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11988170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11988170</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00675-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11988170">Tanemoto et al. (2002)</a> identified domains responsible for Kir5.1/PSD95 interaction. They reported that protein kinase A (PKA)-mediated phosphorylation of Kir5.1 disrupted the binding of Kir5.1 with PSD95. <a href="#24" class="mim-tip-reference" title="Tanemoto, M., Fujita, A., Higashi, K., Kurachi, Y. <strong>PSD-95 mediates formation of a functional homomeric Kir5.1 channel in the brain.</strong> Neuron 34: 387-397, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11988170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11988170</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00675-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11988170">Tanemoto et al. (2002)</a> hypothesized that Kir5.1/PSD95 forms a functional brain potassium channel that may be a physiologic target of PKA-mediated signaling. They concluded that PSD95 mediates formation of a functional potassium channel in the brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11988170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Conroy, W. G., Liu, Z., Nai, Q., Coggan, J. S., Berg, D. K. <strong>PDZ-containing proteins provide a functional postsynaptic scaffold for nicotinic receptors in neurons.</strong> Neuron 38: 759-771, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12797960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12797960</a>] [<a href="https://doi.org/10.1016/s0896-6273(03)00324-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12797960">Conroy et al. (2003)</a> showed that PDZ-containing proteins of the Psd95 family were required for maturation of functional nicotinic synapses in embryonic chicken ciliary ganglia. These proteins also helped mediate downstream activation of transcription factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12797960" 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="Colledge, M., Snyder, E. M., Crozier, R. A., Soderling, J. A., Jin, Y., Langeberg, L. K., Lu, H., Bear, M. F., Scott, J. D. <strong>Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression.</strong> Neuron 40: 595-607, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14642282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14642282</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14642282[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/s0896-6273(03)00687-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14642282">Colledge et al. (2003)</a> found that Psd95 interacted with and was ubiquitinated by the E3 ligase Mdm2 (<a href="/entry/164785">164785</a>). In response to NMDA receptor activation in cultured rat hippocampal neurons, Psd95 was ubiquitinated and rapidly removed from synaptic sites by proteasome-dependent degradation. Mutations that blocked Psd95 ubiquitination prevented NMDA-induced AMPA receptor endocytosis. Likewise, proteasome inhibitors prevented NMDA-induced AMPA receptor internalization and synaptically induced long-term depression. <a href="#5" class="mim-tip-reference" title="Colledge, M., Snyder, E. M., Crozier, R. A., Soderling, J. A., Jin, Y., Langeberg, L. K., Lu, H., Bear, M. F., Scott, J. D. <strong>Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression.</strong> Neuron 40: 595-607, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14642282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14642282</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14642282[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/s0896-6273(03)00687-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14642282">Colledge et al. (2003)</a> concluded that ubiquitination of PSD95 through an MDM2-mediated pathway regulates AMPA receptor surface expression during synaptic plasticity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14642282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Bao, J., Lin, H., Ouyang, Y., Lei, D., Osman, A., Kim, T.-W., Mei, L., Dai, P., Ohlemiller, K. K., Ambron, R. T. <strong>Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos.</strong> Nature Neurosci. 7: 1250-1258, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15494726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15494726</a>] [<a href="https://doi.org/10.1038/nn1342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15494726">Bao et al. (2004)</a> found that sound-induced synaptic activity in the mouse cochlea increased the level of nuclear neuregulin-1 intracellular domain (Nrg-ICD) and upregulated PSD95 in postsynaptic spiral ganglion neurons. Nrg-ICD enhanced the transcriptional activity of the PSD95 promoter by binding to Eos (<a href="/entry/606239">606239</a>), a zinc finger transcription factor. The findings identified a molecular basis for activity-dependent synaptic plasticity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15494726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By yeast 2-hybrid analysis of a mouse brain cDNA library, <a href="#18" class="mim-tip-reference" title="Li, Z., Benard, O., Margolskee, R. F. <strong>G-gamma-13 interacts with PDZ domain-containing proteins.</strong> J. Biol. Chem. 281: 11066-11073, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16473877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16473877</a>] [<a href="https://doi.org/10.1074/jbc.M600113200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16473877">Li et al. (2006)</a> found that Gng13 (<a href="/entry/607298">607298</a>) interacted with Psd95. Mutation analysis showed that the interaction involved the third PDZ domain of Psd95 and the C-terminal CAAX motif of Gng13. Coexpression of Gng13 with its G protein partner, Gnb1 (<a href="/entry/139380">139380</a>), did not interfere with the interaction. Coimmunoprecipitation analysis confirmed the interaction between Psd95 and Gng13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16473877" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Aartsen, W. M., Kantardzhieva, A., Klooster, J., van Rossum, A. G. S. H., van de Pavert, S. A., Versteeg, I., Cardozo, B. N., Tonagel, F., Beck, S. C., Tanimoto, N., Seeliger, M. W., Wijnholds, J. <strong>Mpp4 recruits Psd95 and Veli3 towards the photoreceptor synapse.</strong> Hum. Molec. Genet. 15: 1291-1302, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16520334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16520334</a>] [<a href="https://doi.org/10.1093/hmg/ddl047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16520334">Aartsen et al. (2006)</a> found that Mpp4 -/- mouse retinas showed downregulation of Psd95 and mislocalization of both Psd95 and Veli3 (LIN7C; <a href="/entry/612332">612332</a>) at the photoreceptor presynaptic membrane. They proposed that MPP4 may function as a recruitment factor to organize signal transducers at the photoreceptor synapse. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16520334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Kim, M. J., Futai, K., Jo, J., Hayashi, Y., Cho, K., Sheng, M. <strong>Synaptic accumulation of PSD-95 and synaptic function regulated by phosphorylation of serine-295 of PSD-95.</strong> Neuron 56: 488-502, 2007. Note: Erratum: Neuron 57: 326-327, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17988632/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17988632</a>] [<a href="https://doi.org/10.1016/j.neuron.2007.09.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17988632">Kim et al. (2007)</a> showed that phosphorylation of Psd95 in rat hippocampal neurons enhanced Psd95 synaptic accumulation and the ability of Psd95 to recruit surface AMPA receptors and potentiate excitatory postsynaptic currents. They determined that the Rac1 (<a href="/entry/602048">602048</a>)-Jnk1 (MAPK8; <a href="/entry/601158">601158</a>) signaling pathway mediated this phosphorylation. Overexpression of a phosphomimicking mutant of Psd95 inhibited NMDA-induced AMPA receptor internalization and blocked induction of long-term depression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17988632" 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 PSD95 inhibitors, which uncouple postsynaptic density protein PSD95 from neurotoxic signaling pathways, in gyrencephalic nonhuman primates (cynomolgus macaques), <a href="#7" class="mim-tip-reference" title="Cook, D. J., Teves, L., Tymianski, M. <strong>Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain.</strong> Nature 483: 213-217, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22388811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22388811</a>] [<a href="https://doi.org/10.1038/nature10841" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22388811">Cook et al. (2012)</a> showed that stroke damage can be prevented when a PSD95 inhibitor is administered after stroke onset in clinically relevant situations. The treatment reduced infarct volumes as gauged by MRI and histology, preserved the capacity of ischemic cells to maintain gene transcription in genomewide screens of ischemic brain tissue, and significantly preserved neurologic function in neurobehavioral assays. The degree of tissue neuroprotection by MRI corresponded strongly to the preservation of neurologic function, supporting the intuitive but unproven dictum that integrity of brain tissue can reflect functional outcome. <a href="#7" class="mim-tip-reference" title="Cook, D. J., Teves, L., Tymianski, M. <strong>Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain.</strong> Nature 483: 213-217, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22388811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22388811</a>] [<a href="https://doi.org/10.1038/nature10841" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22388811">Cook et al. (2012)</a> concluded that their findings established that tissue neuroprotection and improved functional outcome after stroke is unequivocally achievable in gyrencephalic nonhuman primates treated with PSD95 inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22388811" 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="#23" class="mim-tip-reference" title="Stathakis, D. G., Udar, N., Sandgren, O., Andreasson, S., Bryant, P. J., Small, K., Forsman-Semb, K. <strong>Genomic organization of human DLG4, the gene encoding postsynaptic density 95.</strong> J. Neurochem. 73: 2250-2265, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10582582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10582582</a>] [<a href="https://doi.org/10.1046/j.1471-4159.1999.0732250.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10582582">Stathakis et al. (1999)</a> determined that the DLG4 gene contains 22 exons and spans about 30 kb. All splice sites conform to the GT-AG rule, except for the splice acceptor site of intron 5, which is TG instead of AG. The promoter region contains no TATA or CAAT boxes, but has a large GC-rich domain with characteristics of a CpG island. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10582582" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Zhang, L.-F., Ding, J.-H., Yang, B.-Z., He, G.-C., Roe, C. <strong>Characterization of the bidirectional promoter region between the human genes encoding VLCAD and PSD-95.</strong> Genomics 82: 660-668, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14611808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14611808</a>] [<a href="https://doi.org/10.1016/s0888-7543(03)00211-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14611808">Zhang et al. (2003)</a> noted that the VLCAD (<a href="/entry/609575">609575</a>) and the DLG4 genes are located in a head-to-head orientation on chromosome 17p. The transcribed regions of the 2 genes overlap by about 220 bp. Using serial promoter partial deletion constructs in a reporter gene assay, they found that the essential promoter activity of DLG4 is carried within a region of about 400 bp and covers the entire VLCAD minimal promoter, which spans about 270 bp. The results from di-(2-ethylhexyl) phthalate (DEHP)-treated HepG2 cells revealed that the minimal VLCAD promoter can upregulate VLCAD expression in response to DEHP treatment. Site-directed mutagenesis experiments showed that a mutated AP2 (<a href="/entry/107580">107580</a>)-binding site markedly reduced the transcriptional activity of both the VLCAD and DLG4 promoters and abolished the minimal VLCAD promoter's response to DEHP treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14611808" 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>Independently, <a href="#27" class="mim-tip-reference" title="Zhou, C., Blumberg, B. <strong>Overlapping gene structure of human VLCAD and DLG4.</strong> Gene 305: 161-166, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12609736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12609736</a>] [<a href="https://doi.org/10.1016/s0378-1119(02)01235-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12609736">Zhou and Blumberg (2003)</a> determined that the VLCAD and DLG4 genes overlap. The 2 genes share 245 nucleotides at their 5-prime ends, and the transcription start site for DLG4 extends into the coding region of VLCAD exon 1. The upstream regions of the VLCAD and DLG4 genes, including the overlapping region, contain 2 potential TATA-less promoters with potential binding sites for several common transcription factors. RT-PCR detected unique patterns of expression for VLCAD and DLG4, indicating that, although they share common regulatory elements, VLCAD and DLG4 also have distinct tissue-specific elements. The mouse Dlg4 and Vlcad genes are oriented in a head-to-head manner, but they do not overlap and are separated by almost 3.5 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12609736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By radiation hybrid mapping, <a href="#22" class="mim-tip-reference" title="Stathakis, D. G., Hoover, K. B., You, Z., Bryant, P. J. <strong>Human postsynaptic density-95 (PSD95): location of the gene (DLG4) and possible function in nonneural as well as in neural tissues.</strong> Genomics 44: 71-82, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9286702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9286702</a>] [<a href="https://doi.org/10.1006/geno.1997.4848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9286702">Stathakis et al. (1997)</a> localized the DLG4 gene to chromosome 17p13.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9286702" 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 3 unrelated patients with autosomal dominant intellectual developmental disorder-62 (MRD62; <a href="/entry/618793">618793</a>), <a href="#17" class="mim-tip-reference" title="Lelieveld, S. H., Reijnders, M. R. F., Pfundt, R., Yntema, H. G., Kamsteeg, E.-J., de Vries, P., de Vries, B. B. A., Willemsen, M. H., Kleefstra, T., Lohner, K., Vreeburg, M., Stevens, S. J. C., and 10 others. <strong>Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.</strong> Nature Neurosci. 19: 1194-1196, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27479843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27479843</a>] [<a href="https://doi.org/10.1038/nn.4352" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27479843">Lelieveld et al. (2016)</a> identified 3 different de novo heterozygous frameshift or nonsense mutations in the DLG4 gene (<a href="#0001">602887.0001</a>-<a href="#0003">602887.0003</a>). The mutations, which were found by trio-based exome sequencing and confirmed by Sanger sequencing, were not found in the dbSNP (build 137) database. Functional studies of the variants and studies of patient cells were not performed, but all variants were predicted to result in haploinsufficiency. The patients were ascertained from a cohort of 820 individuals with intellectual disability who underwent trio-based exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27479843" 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 3 unrelated adult males with MRD62, <a href="#20" class="mim-tip-reference" title="Moutton, S., Bruel, A.-L., Assoum, M., Chevarin, M., Sarrazin, E., Goizet, C., Guerrot, A. M., Charollais, A., Charles, P., Heron, D., Faudet, A., Houcinat, N., Vitobello, A., Tran-Mau-Them, F., Philippe, C., Duffourd, Y., Thauvin-Robinet, C., Faivre, L. <strong>Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features.</strong> Clin. Genet. 93: 1172-1178, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29460436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29460436</a>] [<a href="https://doi.org/10.1111/cge.13243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29460436">Moutton et al. (2018)</a> identified heterozygous loss-of-function mutations in the DLG4 gene (<a href="#0004">602887.0004</a>-<a href="#0006">602887.0006</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in public databases, including gnomAD. The mutations occurred de novo in 2 patients; paternal DNA from the third patient was not available. Analysis of cells derived from 2 patients showed a 50% decrease in mRNA, suggesting that the mutation resulted in nonsense-mediated mRNA decay. Cells derived from the third patient, who had a splice site mutation, suggested production of an abnormal mRNA that would result in premature protein termination. The patients were ascertained from a cohort of 64 individuals with intellectual disability who also had some clinical marfanoid features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29460436" 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>Specific patterns of neuronal firing induce changes in synaptic strength that may contribute to learning and memory. If the postsynaptic NMDA receptors are blocked, long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission and the learning of spatial information are prevented. The NMDA receptor can bind PSD95, which may regulate the localization of and/or signaling by the receptor. <a href="#19" class="mim-tip-reference" title="Migaud, M., Charlesworth, P., Dempster, M., Webster, L. C., Watabe, A. M., Makhinson, M., He, Y., Ramsay, M. F., Morris, R. G. M., Morrison, J. H., O'Dell, T. J., Grant, S. G. N. <strong>Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein.</strong> Nature 396: 433-439, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9853749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9853749</a>] [<a href="https://doi.org/10.1038/24790" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9853749">Migaud et al. (1998)</a> found that in mutant mice lacking Psd95, the frequency function of NMDA-dependent LTP and LTD was shifted to produce strikingly enhanced LTP at different frequencies of synaptic stimulation. In keeping with neural-network models that incorporate bidirectional learning rules, this frequency shift was accompanied by severely impaired spatial learning. Synaptic NMDA-receptor currents, subunit expression, localization, and synaptic morphology were all unaffected in the mutant mice. PSD95 thus appears to be important in coupling the NMDA receptor to pathways that control bidirectional synaptic plasticity and learning. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9853749" 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 microarray analysis, <a href="#25" class="mim-tip-reference" title="Yao, W.-D., Gainetdinov, R. R., Arbuckle, M. I., Sotnikova, T. D., Cyr, M., Beaulieu, J.-M., Torres, G. E., Grant, S. G. N., Caron, M. G. <strong>Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity.</strong> Neuron 41: 625-638, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14980210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14980210</a>] [<a href="https://doi.org/10.1016/s0896-6273(04)00048-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14980210">Yao et al. (2004)</a> identified Psd95 among a small number of genes whose expression was downregulated in Dat (SLC6A3; <a href="/entry/126455">126455</a>) -/- mice, Net (SLC6A2; <a href="/entry/163970">163970</a>) -/- mice, and Vmat2 (SLC18A2; <a href="/entry/193001">193001</a>) +/- mice, all of which are models of dopamine supersensitivity, as well as in mice chronically treated with cocaine. In all 4 models, Psd95 mRNA and protein levels were downregulated in nucleus accumbens and caudate putamen. Psd95 protein was also decreased specifically in striatum, but not in cortex and hippocampus, of cocaine-treated animals. Enhanced long-term potentiation of frontocortico-accumbal glutamatergic synapses correlated with reduced Psd95 levels in all 4 models. <a href="#25" class="mim-tip-reference" title="Yao, W.-D., Gainetdinov, R. R., Arbuckle, M. I., Sotnikova, T. D., Cyr, M., Beaulieu, J.-M., Torres, G. E., Grant, S. G. N., Caron, M. G. <strong>Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity.</strong> Neuron 41: 625-638, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14980210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14980210</a>] [<a href="https://doi.org/10.1016/s0896-6273(04)00048-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14980210">Yao et al. (2004)</a> also found that Psd95 -/- mice were supersensitive to cocaine and lacked chronic cocaine-induced behavioral plasticity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14980210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Beique, J.-C., Lin, D.-T., Kang, M.-G., Aizawa, H., Takamiya, K., Huganir, R. L. <strong>Synapse-specific regulation of AMPA receptor function by PSD-95.</strong> Proc. Nat. Acad. Sci. 103: 19535-19540, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17148601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17148601</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17148601[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0608492103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17148601">Beique et al. (2006)</a> found that Psd95-null mice had decreased glutamate AMPA receptor-mediated synaptic transmission but NMDA receptors were not affected. Although most of the affected synapses were located on morphologically mature dendritic spines, a significant population of synapses appeared unaffected by Psd95 depletion, suggesting that the functional role of Psd95 displays synapse specificity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17148601" 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="#10" class="mim-tip-reference" title="Feyder, M., Karlsson, R.-M., Mathur, P., Lyman, M., Bock, R., Momenan, R., Munasinghe, J., Scattoni, M. L., Ihne, J., Camp, M., Graybeal, C., Strathdee, D., and 9 others. <strong>Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams' syndrome.</strong> Am. J. Psychiat. 167: 1508-1517, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20952458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20952458</a>] [<a href="https://doi.org/10.1176/appi.ajp.2010.10040484" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20952458">Feyder et al. (2010)</a> found that Dlg4-null mice showed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses compared to controls. Mutant mice also had subtle morphologic dendritic anomalies in the basolateral amygdala and altered forebrain expression of various synaptic genes. The phenotypic findings were reminiscent of autism spectrum disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20952458" 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 patient (patient 77) with autosomal dominant intellectual developmental disorder-62 (MRD62; <a href="/entry/618793">618793</a>), <a href="#17" class="mim-tip-reference" title="Lelieveld, S. H., Reijnders, M. R. F., Pfundt, R., Yntema, H. G., Kamsteeg, E.-J., de Vries, P., de Vries, B. B. A., Willemsen, M. H., Kleefstra, T., Lohner, K., Vreeburg, M., Stevens, S. J. C., and 10 others. <strong>Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.</strong> Nature Neurosci. 19: 1194-1196, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27479843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27479843</a>] [<a href="https://doi.org/10.1038/nn.4352" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27479843">Lelieveld et al. (2016)</a> identified a de novo heterozygous 1-bp duplication (c.277dupA, NM_001365.3) in the DLG4 gene, predicted to result in a frameshift and premature termination (Y93fs). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137) database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27479843" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1597452702 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1597452702;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1597452702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1597452702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient (patient 706) with autosomal dominant intellectual developmental disorder-62 (MRD62; <a href="/entry/618793">618793</a>), <a href="#17" class="mim-tip-reference" title="Lelieveld, S. H., Reijnders, M. R. F., Pfundt, R., Yntema, H. G., Kamsteeg, E.-J., de Vries, P., de Vries, B. B. A., Willemsen, M. H., Kleefstra, T., Lohner, K., Vreeburg, M., Stevens, S. J. C., and 10 others. <strong>Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.</strong> Nature Neurosci. 19: 1194-1196, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27479843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27479843</a>] [<a href="https://doi.org/10.1038/nn.4352" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27479843">Lelieveld et al. (2016)</a> identified a de novo heterozygous c.1231C-T transition (c.1231C-T, NM_001365.3) in the DLG4 gene, resulting in an arg411-to-ter (R411X) substitution. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137) database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27479843" 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 patient (patient 747) with autosomal dominant intellectual developmental disorder-62 (MRD62; <a href="/entry/618793">618793</a>), <a href="#17" class="mim-tip-reference" title="Lelieveld, S. H., Reijnders, M. R. F., Pfundt, R., Yntema, H. G., Kamsteeg, E.-J., de Vries, P., de Vries, B. B. A., Willemsen, M. H., Kleefstra, T., Lohner, K., Vreeburg, M., Stevens, S. J. C., and 10 others. <strong>Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.</strong> Nature Neurosci. 19: 1194-1196, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27479843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27479843</a>] [<a href="https://doi.org/10.1038/nn.4352" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27479843">Lelieveld et al. (2016)</a> identified a de novo heterozygous c.1054C-T transition (c.1054C-T, NM_001365.3) in the DLG4 gene, resulting in an arg352-to-ter (R352X) substitution. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137) database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27479843" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1597442444 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1597442444;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1597442444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1597442444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 23-year-old French man (patient 1) with autosomal dominant intellectual developmental disorder-62 (MRD62; <a href="/entry/618793">618793</a>), <a href="#20" class="mim-tip-reference" title="Moutton, S., Bruel, A.-L., Assoum, M., Chevarin, M., Sarrazin, E., Goizet, C., Guerrot, A. M., Charollais, A., Charles, P., Heron, D., Faudet, A., Houcinat, N., Vitobello, A., Tran-Mau-Them, F., Philippe, C., Duffourd, Y., Thauvin-Robinet, C., Faivre, L. <strong>Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features.</strong> Clin. Genet. 93: 1172-1178, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29460436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29460436</a>] [<a href="https://doi.org/10.1111/cge.13243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29460436">Moutton et al. (2018)</a> identified a de novo heterozygous 1-bp deletion (c.1843delG, NM_001365.3) in exon 19 of the DLG4 gene, resulting in a frameshift and premature termination (Glu615SerfsTer4). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in public databases, including gnomAD. Analysis of patient cells showed a 50% decrease in mRNA, suggesting that the mutation resulted in nonsense-mediated mRNA decay. The findings were consistent with haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29460436" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1597453595 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1597453595;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1597453595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1597453595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 21-year-old man (patient 2) of French and Portuguese descent with autosomal dominant intellectual developmental disorder-62 (MRD62; <a href="/entry/618793">618793</a>), <a href="#20" class="mim-tip-reference" title="Moutton, S., Bruel, A.-L., Assoum, M., Chevarin, M., Sarrazin, E., Goizet, C., Guerrot, A. M., Charollais, A., Charles, P., Heron, D., Faudet, A., Houcinat, N., Vitobello, A., Tran-Mau-Them, F., Philippe, C., Duffourd, Y., Thauvin-Robinet, C., Faivre, L. <strong>Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features.</strong> Clin. Genet. 93: 1172-1178, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29460436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29460436</a>] [<a href="https://doi.org/10.1111/cge.13243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29460436">Moutton et al. (2018)</a> identified a de novo heterozygous 8-bp deletion (c.1147_1154del, NM_001365.3) in exon 11 of the DLG4 gene, resulting in a frameshift and premature termination (Phe383GlyfsTer31) in the PDZ3 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in public databases, including gnomAD. Analysis of patient cells showed a 50% decrease in mRNA, suggesting that the mutation resulted in nonsense-mediated mRNA decay. The findings were consistent with haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29460436" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1597444614 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1597444614;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1597444614" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1597444614" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 35-year-old man (patient 3) with autosomal dominant intellectual developmental disorder-62 (MRD62; <a href="/entry/618793">618793</a>), <a href="#20" class="mim-tip-reference" title="Moutton, S., Bruel, A.-L., Assoum, M., Chevarin, M., Sarrazin, E., Goizet, C., Guerrot, A. M., Charollais, A., Charles, P., Heron, D., Faudet, A., Houcinat, N., Vitobello, A., Tran-Mau-Them, F., Philippe, C., Duffourd, Y., Thauvin-Robinet, C., Faivre, L. <strong>Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features.</strong> Clin. Genet. 93: 1172-1178, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29460436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29460436</a>] [<a href="https://doi.org/10.1111/cge.13243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29460436">Moutton et al. (2018)</a> identified a heterozygous T-to-C transition (c.1672+2T-C, NM_001365.3) in intron 16 of the DLG4 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in public databases, including gnomAD. The variant was not found in the mother; DNA from the father was unavailable. Analysis of patient cells showed that the mutation caused aberrant splicing predicted to result in a frameshift and premature termination (Gly558ProfsTer37). This change would cause disruption of the guanylate kinase domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29460436" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1073/pnas.97.7.3596" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0896-6273(00)81176-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2007.09.007" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/24790" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0896-6273(04)00048-0" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14611808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14611808</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14611808" 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/s0888-7543(03)00211-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0378-1119(02)01235-0" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 02/26/2020
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Ada Hamosh - updated : 5/15/2012<br>Patricia A. Hartz - updated : 5/3/2011<br>Patricia A. Hartz - updated : 10/28/2010<br>Matthew B. Gross - updated : 10/12/2009<br>Patricia A. Hartz - updated : 10/8/2009<br>Cassandra L. Kniffin - updated : 3/29/2007<br>Cassandra L. Kniffin - updated : 2/14/2005<br>Patricia A. Hartz - updated : 12/29/2003<br>Dawn Watkins-Chow - updated : 12/18/2002<br>Stylianos E. Antonarakis - updated : 5/6/2002<br>Ada Hamosh - updated : 5/1/2001<br>Ada Hamosh - updated : 11/30/2000<br>Ada Hamosh - updated : 6/11/1999<br>Rebekah S. Rasooly - updated : 2/24/1999<br>Victor A. McKusick - updated : 12/10/1998
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carol : 02/28/2020<br>carol : 02/27/2020<br>ckniffin : 02/26/2020<br>carol : 09/06/2019<br>mgross : 08/26/2016<br>terry : 04/04/2013<br>alopez : 5/16/2012<br>terry : 5/15/2012<br>mgross : 5/18/2011<br>terry : 5/3/2011<br>mgross : 11/10/2010<br>terry : 10/28/2010<br>mgross : 10/12/2009<br>terry : 10/8/2009<br>alopez : 6/21/2007<br>terry : 6/15/2007<br>wwang : 3/30/2007<br>ckniffin : 3/29/2007<br>ckniffin : 9/22/2005<br>wwang : 2/23/2005<br>ckniffin : 2/14/2005<br>carol : 12/29/2003<br>tkritzer : 12/18/2002<br>tkritzer : 12/18/2002<br>terry : 11/15/2002<br>mgross : 5/6/2002<br>mcapotos : 5/8/2001<br>mcapotos : 5/4/2001<br>terry : 5/1/2001<br>carol : 12/1/2000<br>terry : 11/30/2000<br>alopez : 6/11/1999<br>alopez : 5/7/1999<br>mgross : 3/17/1999<br>psherman : 2/24/1999<br>alopez : 12/10/1998<br>terry : 12/10/1998<br>alopez : 7/28/1998<br>alopez : 7/27/1998
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<h3>
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<span class="mim-font">
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<strong>*</strong> 602887
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</h3>
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<h3>
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<span class="mim-font">
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DISCS LARGE MAGUK SCAFFOLD PROTEIN 4; DLG4
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</h3>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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<h4>
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<span class="mim-font">
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DISCS LARGE, DROSOPHILA, HOMOLOG OF, 4<br />
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POSTSYNAPTIC DENSITY 95; PSD95<br />
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SYNAPSE-ASSOCIATED PROTEIN 90; SAP90
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</h4>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: DLG4</em></strong>
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</span>
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</p>
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</div>
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<strong>
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<em>
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Cytogenetic location: 17p13.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 17:7,187,187-7,220,050 </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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<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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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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<th>
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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</th>
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Phenotype <br /> mapping key
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<tbody>
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<td rowspan="1">
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<span class="mim-font">
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17p13.1
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<span class="mim-font">
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Intellectual developmental disorder, autosomal dominant 62
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</td>
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<span class="mim-font">
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618793
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<span class="mim-font">
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>DLG4 belongs to the discs large (DLG) subfamily of the membrane-associated guanylate kinase (MAGUK) family (see DLG1; 601014). DLG4 interacts with both N-methyl-D-aspartate (NMDA) receptors (see 138249) and Shaker-type potassium channels (see 176260) and plays an important role in the formation and maintenance of synaptic junctions (Zhou and Blumberg, 2003). </p>
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<strong>Cloning and Expression</strong>
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</h4>
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<p>Proteins related to Drosophila 'discs large' (Dlg) are associated with the cortical actin cytoskeleton and appear to have both structural and functional roles. By screening a human mammary gland cDNA library with a human EST showing homology to rat Psd95, which is also known as Sap90 (Kistner et al., 1993), Stathakis et al. (1997) cloned a cDNA encoding DLG4, which they called PSD95. The predicted 723-amino acid DLG4 protein has 3 PSD95-DLG-Z01 (PDZ) domains in its N-terminal half, a central src homology-3 (SH3) motif, and a C-terminal guanylate kinase (GUK)-homologous domain. The human DLG4 protein is 99% identical to the rat and mouse Psd95 proteins and 56% identical to the Drosophila Dlg protein. Northern blot analysis detected 6 DLG4 transcripts with different expression patterns, including a 4.2-kb transcript that was variably expressed in all 17 human tissues examined. Western blot analysis using antibodies against DLG4 detected multiple proteins with complex distribution patterns, including a ubiquitous 85-kD and tissue-specific variants. </p><p>By examining human brain, mammary gland, pancreas, and testis cDNA libraries, Stathakis et al. (1999) identified 3 splice variants of DLG4. A transcript lacking exon 3 was detected in brain, but not in other tissues. This variant introduces an early frameshift and encodes a predicted 45-amino acid peptide. However, a downstream ORF from exons 4 through 22 has the potential to encode a 664-amino acid protein containing all functional domains of DLG4, with a single residue before the first PDZ domain. A variant lacking exon 20 was detected in mammary gland and testis, but not in brain or pancreas. This variant encodes a deduced 670-amino acid protein that lacks part of the C-terminal GUK domain. A variant containing a 99-nucleotide extension of exon 4 (exon 4b) was detected in testis, but not in other tissues. This variant encodes a deduced 803-amino acid protein with 33 additional amino acids inserted before the first PDZ domain. </p><p>Zhou and Blumberg (2003) stated that the N terminus of DLG4 is modified by thioester-linked palmitate, which targets the protein to cell membranes. Palmitoylation is also a critical regulatory mechanism for receptor interactions with DLG4. Real-time RT-PCR detected DLG4 expression in all tissues examined, with highest expression in brain, followed by heart, placenta, lung, pancreas, spleen, thymus, testis, ovary, and small intestine. </p>
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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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</h4>
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<span class="mim-text-font">
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<p>The proper distribution of voltage-gated and ligand-gated ion channels on the neuronal surface is critical for the processing and transmission of electrical signals in neurons. Kim et al. (1995) and Kim et al. (1996) demonstrated that PSD95 and chapsyn-110 (603583) mediated clustering of both NMDA receptors and potassium channels. Chapsyn-110 and PSD95 heteromultimerized with each other and were recruited into the same NMDA receptor and potassium channel clusters. Kim et al. (1996) suggested that these 2 proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins. </p><p>In cultured cortical neurons, Sattler et al. (1999) suppressed expression of the NMDA receptor scaffolding protein PSD95 and observed selective attenuation of excitotoxicity triggered via NMDA receptors, but not by other glutamate or calcium ion channels. NMDA receptor function was unaffected because receptor expression, NMDA currents, and calcium-45 loading were unchanged. Suppressing PSD95 blocked calcium-activated nitric oxide production by NMDA receptors selectively without affecting neuronal nitric oxide synthase expression or function. Thus, PSD95 is required for efficient coupling of NMDAR activity to nitric oxide toxicity and imparts specificity to excitotoxic calcium signaling. </p><p>El-Husseini et al. (2000) found that overexpression of PSD95 in hippocampal neurons could drive maturation of glutamatergic synapses. PSD95 expression enhanced postsynaptic clustering and activity of glutamate receptors. Postsynaptic expression of PSD95 also enhanced maturation of the presynaptic terminal. These effects required synaptic clustering of PSD95 but did not rely on its guanylate kinase domain. PSD95 expression also increased the number and size of dendritic spines. El-Husseini et al. (2000) concluded that PSD95 can orchestrate synaptic development and suggested that PSD95 has a role in synapse stabilization and plasticity. </p><p>Neuregulins and their receptors, the ERBB protein tyrosine kinases, are essential for neuronal development, but their functions in the adult central nervous system are unknown. Huang et al. (2000) reported that ERBB4 (600543) is enriched in the postsynaptic density and associates with PSD95. Heterologous expression of PSD95 enhanced NRG (142445) activation of ERBB4 and MAP kinase (see 176948). Conversely, inhibiting expression of PSD95 in neurons attenuated NRG-mediated activation of MAP kinase. PSD95 formed a ternary complex with 2 molecules of ERBB4, suggesting that PSD95 facilitates ERBB4 dimerization. Finally, NRG suppressed induction of long-term potentiation in the hippocampal CA1 region without affecting basal synaptic transmission. Thus, NRG signaling may be synaptic and regulated by PSD95. Huang et al. (2000) concluded that a role of NRG signaling in the adult central nervous system may be modulation of synaptic plasticity. </p><p>Garcia et al. (2000) found that Erbb4 and Psd95 coimmunoprecipitated from rat forebrain lysates and that the direct interaction was mediated through the C-terminal end of Erbb4. Immunofluorescent studies of cultured rat hippocampal cells showed that Erbb4 colocalized with Psd95 and NMDA receptors at interneuronal postsynaptic sites. The findings suggested that certain ERBB receptors interact with other receptors and may be important in activity-dependent synaptic plasticity. </p><p>El-Husseini et al. (2002) identified palmitate cycling on PSD95 at the synapse and found that palmitate turnover on PSD95 is regulated by glutamate receptor activity. Acutely blocking palmitoylation dispersed synaptic clusters of PSD95 and caused a selective loss of synaptic AMPA receptors (e.g., GRIA1; 138248). The authors also found that rapid glutamate-mediated AMPA receptor internalization requires depalmitoylation of PSD95. In a nonneuronal model system, clustering of PSD95, stargazin (602911), and AMPA receptors was also regulated by ongoing palmitoylation of PSD95 at the plasma membrane. El-Husseini et al. (2002) concluded that palmitate cycling on PSD95 can regulate synaptic strength and activity-dependent plasticity. </p><p>To treat stroke without blocking NMDA receptors, Aarts et al. (2002) transduced neurons with peptides that disrupted the interaction of NMDA receptors with the postsynaptic density protein PSD95. This procedure dissociated NMDA receptors from downstream neurotoxic signaling without blocking synaptic activity or calcium influx. The peptides, when applied either before or 1 hour after an insult, protected cultured neurons from excitotoxicity, reduced focal ischemic brain damage in rats, and improved their neurologic function. Aarts et al. (2002) concluded that their approach circumvents the negative consequences associated with blocking NMDA receptors and may constitute a practical stroke therapy. </p><p>In cotransfection experiments, Tanemoto et al. (2002) showed that Kir5.1 (KCNJ16; 605722) assembled to form a functional homomeric potassium channel by interacting with PSD95. The authors observed that Kir5.1 expressed alone was distributed mostly in the cytoplasm, but Kir5.1 coexpressed with PSD95 was located on the plasma membrane in a clustered manner. Using GST pull-down studies, Tanemoto et al. (2002) identified domains responsible for Kir5.1/PSD95 interaction. They reported that protein kinase A (PKA)-mediated phosphorylation of Kir5.1 disrupted the binding of Kir5.1 with PSD95. Tanemoto et al. (2002) hypothesized that Kir5.1/PSD95 forms a functional brain potassium channel that may be a physiologic target of PKA-mediated signaling. They concluded that PSD95 mediates formation of a functional potassium channel in the brain. </p><p>Conroy et al. (2003) showed that PDZ-containing proteins of the Psd95 family were required for maturation of functional nicotinic synapses in embryonic chicken ciliary ganglia. These proteins also helped mediate downstream activation of transcription factors. </p><p>Colledge et al. (2003) found that Psd95 interacted with and was ubiquitinated by the E3 ligase Mdm2 (164785). In response to NMDA receptor activation in cultured rat hippocampal neurons, Psd95 was ubiquitinated and rapidly removed from synaptic sites by proteasome-dependent degradation. Mutations that blocked Psd95 ubiquitination prevented NMDA-induced AMPA receptor endocytosis. Likewise, proteasome inhibitors prevented NMDA-induced AMPA receptor internalization and synaptically induced long-term depression. Colledge et al. (2003) concluded that ubiquitination of PSD95 through an MDM2-mediated pathway regulates AMPA receptor surface expression during synaptic plasticity. </p><p>Bao et al. (2004) found that sound-induced synaptic activity in the mouse cochlea increased the level of nuclear neuregulin-1 intracellular domain (Nrg-ICD) and upregulated PSD95 in postsynaptic spiral ganglion neurons. Nrg-ICD enhanced the transcriptional activity of the PSD95 promoter by binding to Eos (606239), a zinc finger transcription factor. The findings identified a molecular basis for activity-dependent synaptic plasticity. </p><p>By yeast 2-hybrid analysis of a mouse brain cDNA library, Li et al. (2006) found that Gng13 (607298) interacted with Psd95. Mutation analysis showed that the interaction involved the third PDZ domain of Psd95 and the C-terminal CAAX motif of Gng13. Coexpression of Gng13 with its G protein partner, Gnb1 (139380), did not interfere with the interaction. Coimmunoprecipitation analysis confirmed the interaction between Psd95 and Gng13. </p><p>Aartsen et al. (2006) found that Mpp4 -/- mouse retinas showed downregulation of Psd95 and mislocalization of both Psd95 and Veli3 (LIN7C; 612332) at the photoreceptor presynaptic membrane. They proposed that MPP4 may function as a recruitment factor to organize signal transducers at the photoreceptor synapse. </p><p>Kim et al. (2007) showed that phosphorylation of Psd95 in rat hippocampal neurons enhanced Psd95 synaptic accumulation and the ability of Psd95 to recruit surface AMPA receptors and potentiate excitatory postsynaptic currents. They determined that the Rac1 (602048)-Jnk1 (MAPK8; 601158) signaling pathway mediated this phosphorylation. Overexpression of a phosphomimicking mutant of Psd95 inhibited NMDA-induced AMPA receptor internalization and blocked induction of long-term depression. </p><p>Using PSD95 inhibitors, which uncouple postsynaptic density protein PSD95 from neurotoxic signaling pathways, in gyrencephalic nonhuman primates (cynomolgus macaques), Cook et al. (2012) showed that stroke damage can be prevented when a PSD95 inhibitor is administered after stroke onset in clinically relevant situations. The treatment reduced infarct volumes as gauged by MRI and histology, preserved the capacity of ischemic cells to maintain gene transcription in genomewide screens of ischemic brain tissue, and significantly preserved neurologic function in neurobehavioral assays. The degree of tissue neuroprotection by MRI corresponded strongly to the preservation of neurologic function, supporting the intuitive but unproven dictum that integrity of brain tissue can reflect functional outcome. Cook et al. (2012) concluded that their findings established that tissue neuroprotection and improved functional outcome after stroke is unequivocally achievable in gyrencephalic nonhuman primates treated with PSD95 inhibitors. </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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<strong>Gene Structure</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Stathakis et al. (1999) determined that the DLG4 gene contains 22 exons and spans about 30 kb. All splice sites conform to the GT-AG rule, except for the splice acceptor site of intron 5, which is TG instead of AG. The promoter region contains no TATA or CAAT boxes, but has a large GC-rich domain with characteristics of a CpG island. </p><p>Zhang et al. (2003) noted that the VLCAD (609575) and the DLG4 genes are located in a head-to-head orientation on chromosome 17p. The transcribed regions of the 2 genes overlap by about 220 bp. Using serial promoter partial deletion constructs in a reporter gene assay, they found that the essential promoter activity of DLG4 is carried within a region of about 400 bp and covers the entire VLCAD minimal promoter, which spans about 270 bp. The results from di-(2-ethylhexyl) phthalate (DEHP)-treated HepG2 cells revealed that the minimal VLCAD promoter can upregulate VLCAD expression in response to DEHP treatment. Site-directed mutagenesis experiments showed that a mutated AP2 (107580)-binding site markedly reduced the transcriptional activity of both the VLCAD and DLG4 promoters and abolished the minimal VLCAD promoter's response to DEHP treatment. </p><p>Independently, Zhou and Blumberg (2003) determined that the VLCAD and DLG4 genes overlap. The 2 genes share 245 nucleotides at their 5-prime ends, and the transcription start site for DLG4 extends into the coding region of VLCAD exon 1. The upstream regions of the VLCAD and DLG4 genes, including the overlapping region, contain 2 potential TATA-less promoters with potential binding sites for several common transcription factors. RT-PCR detected unique patterns of expression for VLCAD and DLG4, indicating that, although they share common regulatory elements, VLCAD and DLG4 also have distinct tissue-specific elements. The mouse Dlg4 and Vlcad genes are oriented in a head-to-head manner, but they do not overlap and are separated by almost 3.5 kb. </p>
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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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<span class="mim-text-font">
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<p>By radiation hybrid mapping, Stathakis et al. (1997) localized the DLG4 gene to chromosome 17p13.1. </p>
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</span>
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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 class="mim-text-font">
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<p>In 3 unrelated patients with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Lelieveld et al. (2016) identified 3 different de novo heterozygous frameshift or nonsense mutations in the DLG4 gene (602887.0001-602887.0003). The mutations, which were found by trio-based exome sequencing and confirmed by Sanger sequencing, were not found in the dbSNP (build 137) database. Functional studies of the variants and studies of patient cells were not performed, but all variants were predicted to result in haploinsufficiency. The patients were ascertained from a cohort of 820 individuals with intellectual disability who underwent trio-based exome sequencing. </p><p>In 3 unrelated adult males with MRD62, Moutton et al. (2018) identified heterozygous loss-of-function mutations in the DLG4 gene (602887.0004-602887.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in public databases, including gnomAD. The mutations occurred de novo in 2 patients; paternal DNA from the third patient was not available. Analysis of cells derived from 2 patients showed a 50% decrease in mRNA, suggesting that the mutation resulted in nonsense-mediated mRNA decay. Cells derived from the third patient, who had a splice site mutation, suggested production of an abnormal mRNA that would result in premature protein termination. The patients were ascertained from a cohort of 64 individuals with intellectual disability who also had some clinical marfanoid features. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Specific patterns of neuronal firing induce changes in synaptic strength that may contribute to learning and memory. If the postsynaptic NMDA receptors are blocked, long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission and the learning of spatial information are prevented. The NMDA receptor can bind PSD95, which may regulate the localization of and/or signaling by the receptor. Migaud et al. (1998) found that in mutant mice lacking Psd95, the frequency function of NMDA-dependent LTP and LTD was shifted to produce strikingly enhanced LTP at different frequencies of synaptic stimulation. In keeping with neural-network models that incorporate bidirectional learning rules, this frequency shift was accompanied by severely impaired spatial learning. Synaptic NMDA-receptor currents, subunit expression, localization, and synaptic morphology were all unaffected in the mutant mice. PSD95 thus appears to be important in coupling the NMDA receptor to pathways that control bidirectional synaptic plasticity and learning. </p><p>Using microarray analysis, Yao et al. (2004) identified Psd95 among a small number of genes whose expression was downregulated in Dat (SLC6A3; 126455) -/- mice, Net (SLC6A2; 163970) -/- mice, and Vmat2 (SLC18A2; 193001) +/- mice, all of which are models of dopamine supersensitivity, as well as in mice chronically treated with cocaine. In all 4 models, Psd95 mRNA and protein levels were downregulated in nucleus accumbens and caudate putamen. Psd95 protein was also decreased specifically in striatum, but not in cortex and hippocampus, of cocaine-treated animals. Enhanced long-term potentiation of frontocortico-accumbal glutamatergic synapses correlated with reduced Psd95 levels in all 4 models. Yao et al. (2004) also found that Psd95 -/- mice were supersensitive to cocaine and lacked chronic cocaine-induced behavioral plasticity. </p><p>Beique et al. (2006) found that Psd95-null mice had decreased glutamate AMPA receptor-mediated synaptic transmission but NMDA receptors were not affected. Although most of the affected synapses were located on morphologically mature dendritic spines, a significant population of synapses appeared unaffected by Psd95 depletion, suggesting that the functional role of Psd95 displays synapse specificity. </p><p>Feyder et al. (2010) found that Dlg4-null mice showed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses compared to controls. Mutant mice also had subtle morphologic dendritic anomalies in the basolateral amygdala and altered forebrain expression of various synaptic genes. The phenotypic findings were reminiscent of autism spectrum disorders. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>6 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 62</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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DLG4, 1-BP DUP, 277A
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<br />
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SNP: rs869312859,
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ClinVar: RCV000210399, RCV001004848
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient (patient 77) with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Lelieveld et al. (2016) identified a de novo heterozygous 1-bp duplication (c.277dupA, NM_001365.3) in the DLG4 gene, predicted to result in a frameshift and premature termination (Y93fs). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137) database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 62</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DLG4, ARG411TER
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<br />
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SNP: rs1597452702,
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ClinVar: RCV001004849, RCV003329358
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient (patient 706) with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Lelieveld et al. (2016) identified a de novo heterozygous c.1231C-T transition (c.1231C-T, NM_001365.3) in the DLG4 gene, resulting in an arg411-to-ter (R411X) substitution. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137) database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 62</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DLG4, ARG352TER
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<br />
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SNP: rs1182894684,
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ClinVar: RCV001004850, RCV001171614, RCV003396590
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient (patient 747) with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Lelieveld et al. (2016) identified a de novo heterozygous c.1054C-T transition (c.1054C-T, NM_001365.3) in the DLG4 gene, resulting in an arg352-to-ter (R352X) substitution. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137) database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 62</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DLG4, 1-BP DEL, 1843G
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<br />
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SNP: rs1597442444,
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ClinVar: RCV000850477, RCV001004851
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 23-year-old French man (patient 1) with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Moutton et al. (2018) identified a de novo heterozygous 1-bp deletion (c.1843delG, NM_001365.3) in exon 19 of the DLG4 gene, resulting in a frameshift and premature termination (Glu615SerfsTer4). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in public databases, including gnomAD. Analysis of patient cells showed a 50% decrease in mRNA, suggesting that the mutation resulted in nonsense-mediated mRNA decay. The findings were consistent with haploinsufficiency. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0005 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 62</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DLG4, 8-BP DEL, NT1147
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<br />
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SNP: rs1597453595,
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ClinVar: RCV000850478, RCV001004852
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 21-year-old man (patient 2) of French and Portuguese descent with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Moutton et al. (2018) identified a de novo heterozygous 8-bp deletion (c.1147_1154del, NM_001365.3) in exon 11 of the DLG4 gene, resulting in a frameshift and premature termination (Phe383GlyfsTer31) in the PDZ3 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in public databases, including gnomAD. Analysis of patient cells showed a 50% decrease in mRNA, suggesting that the mutation resulted in nonsense-mediated mRNA decay. The findings were consistent with haploinsufficiency. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0006 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 62</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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DLG4, IVS16DS, T-C, +2
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<br />
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SNP: rs1597444614,
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ClinVar: RCV000850484, RCV001004853
|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 35-year-old man (patient 3) with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Moutton et al. (2018) identified a heterozygous T-to-C transition (c.1672+2T-C, NM_001365.3) in intron 16 of the DLG4 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in public databases, including gnomAD. The variant was not found in the mother; DNA from the father was unavailable. Analysis of patient cells showed that the mutation caused aberrant splicing predicted to result in a frameshift and premature termination (Gly558ProfsTer37). This change would cause disruption of the guanylate kinase domain. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
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</h4>
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<div>
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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|
Aarts, M., Liu, Y., Liu, L., Besshoh, S., Arundine, M., Gurd, J. W., Wang, Y.-T., Salter, M. W., Tymianski, M.
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<strong>Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions.</strong>
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Science 298: 846-850, 2002.
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[Full Text: https://doi.org/10.1126/science.1072873]
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Aartsen, W. M., Kantardzhieva, A., Klooster, J., van Rossum, A. G. S. H., van de Pavert, S. A., Versteeg, I., Cardozo, B. N., Tonagel, F., Beck, S. C., Tanimoto, N., Seeliger, M. W., Wijnholds, J.
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<strong>Mpp4 recruits Psd95 and Veli3 towards the photoreceptor synapse.</strong>
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Hum. Molec. Genet. 15: 1291-1302, 2006.
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Bao, J., Lin, H., Ouyang, Y., Lei, D., Osman, A., Kim, T.-W., Mei, L., Dai, P., Ohlemiller, K. K., Ambron, R. T.
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<strong>Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos.</strong>
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Nature Neurosci. 7: 1250-1258, 2004.
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[Full Text: https://doi.org/10.1038/nn1342]
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Beique, J.-C., Lin, D.-T., Kang, M.-G., Aizawa, H., Takamiya, K., Huganir, R. L.
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<strong>Synapse-specific regulation of AMPA receptor function by PSD-95.</strong>
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Proc. Nat. Acad. Sci. 103: 19535-19540, 2006.
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[PubMed: 17148601]
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[Full Text: https://doi.org/10.1073/pnas.0608492103]
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<p class="mim-text-font">
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Colledge, M., Snyder, E. M., Crozier, R. A., Soderling, J. A., Jin, Y., Langeberg, L. K., Lu, H., Bear, M. F., Scott, J. D.
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<strong>Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression.</strong>
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Neuron 40: 595-607, 2003.
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Conroy, W. G., Liu, Z., Nai, Q., Coggan, J. S., Berg, D. K.
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<strong>PDZ-containing proteins provide a functional postsynaptic scaffold for nicotinic receptors in neurons.</strong>
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Neuron 38: 759-771, 2003.
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Cook, D. J., Teves, L., Tymianski, M.
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<strong>Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain.</strong>
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Nature 483: 213-217, 2012.
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[PubMed: 22388811]
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[Full Text: https://doi.org/10.1038/nature10841]
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El-Husseini, A. E.-D., Schnell, E., Chetkovich, D. M., Nicoll, R. A., Bredt, D. S.
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<strong>PSD-95 involvement in maturation of excitatory synapses.</strong>
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Science 290: 1364-1368, 2000.
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[PubMed: 11082065]
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El-Husseini, A. E.-D., Schnell, E., Dakoji, S., Sweeney, N., Zhou, Q., Prange, O., Gauthier-Campbell, C., Aguilera-Moreno, A., Nicoll, R. A., Bredt, D. S.
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<strong>Synaptic strength regulated by palmitate cycling on PSD-95.</strong>
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Cell 108: 849-863, 2002.
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Feyder, M., Karlsson, R.-M., Mathur, P., Lyman, M., Bock, R., Momenan, R., Munasinghe, J., Scattoni, M. L., Ihne, J., Camp, M., Graybeal, C., Strathdee, D., and 9 others.
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<strong>Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams' syndrome.</strong>
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Garcia, R. A. G., Vasudevan, K., Buonanno, A.
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Huang, Y. Z., Won, S., Ali, D. W., Wang, Q., Tanowitz, M., Du, Q. S., Pelkey, K. A., Yang, D. J., Xiong, W. C., Salter, M. W., Mei, L.
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<strong>Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses.</strong>
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Kim, E., Cho, K.-O., Rothschild, A., Sheng, M.
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<strong>Heteromultimerization and NMDA receptor-clustering activity of Chapsyn-110, a member of the PSD-95 family of proteins.</strong>
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Neuron 17: 103-113, 1996.
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Kim, E., Niethammer, M., Rothschild, A., Jan, Y. N., Sheng, M.
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<strong>Clustering of Shaker-type K+ channels by interaction with a family of membrane-associated guanylate kinases.</strong>
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Nature 378: 85-88, 1995.
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[PubMed: 7477295]
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Kim, M. J., Futai, K., Jo, J., Hayashi, Y., Cho, K., Sheng, M.
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<strong>Synaptic accumulation of PSD-95 and synaptic function regulated by phosphorylation of serine-295 of PSD-95.</strong>
|
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Neuron 56: 488-502, 2007. Note: Erratum: Neuron 57: 326-327, 2008.
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[PubMed: 17988632]
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Kistner, U., Wenzel, B. M., Veh, R. W., Cases-Langhoff, C., Garner, A. M., Appeltauer, U., Voss, B., Gundelfinger, E. D., Garner, C. C.
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<strong>SAP90, a rat presynaptic protein related to the product of the Drosophila tumor suppressor gene, dLg-A.</strong>
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J. Biol. Chem. 268: 4580-4583, 1993.
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[PubMed: 7680343]
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<li>
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<p class="mim-text-font">
|
|
Lelieveld, S. H., Reijnders, M. R. F., Pfundt, R., Yntema, H. G., Kamsteeg, E.-J., de Vries, P., de Vries, B. B. A., Willemsen, M. H., Kleefstra, T., Lohner, K., Vreeburg, M., Stevens, S. J. C., and 10 others.
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|
<strong>Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.</strong>
|
|
Nature Neurosci. 19: 1194-1196, 2016.
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[PubMed: 27479843]
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[Full Text: https://doi.org/10.1038/nn.4352]
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</p>
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<li>
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<p class="mim-text-font">
|
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Li, Z., Benard, O., Margolskee, R. F.
|
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<strong>G-gamma-13 interacts with PDZ domain-containing proteins.</strong>
|
|
J. Biol. Chem. 281: 11066-11073, 2006.
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|
[PubMed: 16473877]
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[Full Text: https://doi.org/10.1074/jbc.M600113200]
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</p>
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</li>
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Migaud, M., Charlesworth, P., Dempster, M., Webster, L. C., Watabe, A. M., Makhinson, M., He, Y., Ramsay, M. F., Morris, R. G. M., Morrison, J. H., O'Dell, T. J., Grant, S. G. N.
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<strong>Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein.</strong>
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Nature 396: 433-439, 1998.
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Moutton, S., Bruel, A.-L., Assoum, M., Chevarin, M., Sarrazin, E., Goizet, C., Guerrot, A. M., Charollais, A., Charles, P., Heron, D., Faudet, A., Houcinat, N., Vitobello, A., Tran-Mau-Them, F., Philippe, C., Duffourd, Y., Thauvin-Robinet, C., Faivre, L.
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<strong>Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features.</strong>
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Clin. Genet. 93: 1172-1178, 2018.
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Sattler, R., Xiong, Z., Lu, W.-Y., Hafner, M., MacDonald, J. F., Tymianski, M.
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<strong>Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein.</strong>
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Science 284: 1845-1848, 1999.
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Yao, W.-D., Gainetdinov, R. R., Arbuckle, M. I., Sotnikova, T. D., Cyr, M., Beaulieu, J.-M., Torres, G. E., Grant, S. G. N., Caron, M. G.
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