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Entry
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- *606230 - SH3 AND MULTIPLE ANKYRIN REPEAT DOMAINS 3; SHANK3
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*606230</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<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="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/606230">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000251322;t=ENST00000692848" 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=85358" 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=606230" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000251322;t=ENST00000692848" 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</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001372044" 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://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=606230" 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=18979&isoform_id=18979_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/SHANK3" 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/13359173,18676424,38649051,74418797,299508024,324435597,324435599,324435601,397781855,586830518,1733550831" 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/Q9BYB0" 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=85358" 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=ENSG00000251322;t=ENST00000692848" 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=SHANK3" 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=SHANK3" 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+85358" 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/SHANK3" 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:85358" 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/85358" 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=chr22&hgg_gene=ENST00000692848.2&hgg_start=50672823&hgg_end=50733212&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:14294" 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:14294" 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/shank3" 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=606230[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=606230[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/SHANK3/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/ENSG00000251322" 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=SHANK3" 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=SHANK3" 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=SHANK3" 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=SHANK3&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/PA37866" 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:14294" 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/FBgn0040752.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:1930016" 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/SHANK3#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:1930016" 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/85358/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002402/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=85358" 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=WBGene00006444;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-041210-74" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:85358" 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=SHANK3&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 699310000<br />
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<strong>ICD10CM:</strong> Q93.52<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
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606230
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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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SH3 AND MULTIPLE ANKYRIN REPEAT DOMAINS 3; SHANK3
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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>
|
|
<span class="mim-font">
|
|
PROLINE-RICH SYNAPSE-ASSOCIATED PROTEIN 2; PSAP2<br />
|
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PROSAP2<br />
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KIAA1650
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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=SHANK3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SHANK3</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/22/424?start=-3&limit=10&highlight=424">22q13.33</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr22:50672823-50733212&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'})">22:50,672,823-50,733,212</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>
|
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<br />
|
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</div>
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=613950,606232" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
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</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/22/424?start=-3&limit=10&highlight=424">
|
|
22q13.33
|
|
</a>
|
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
{Schizophrenia 15}
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/613950"> 613950 </a>
|
|
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Phelan-McDermid syndrome
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/606232"> 606232 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
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<p>The SHANK3 gene encodes a scaffolding protein that is enriched in postsynaptic densities of excitatory synapses (summary by <a href="#24" class="mim-tip-reference" title="Yi, F., Danko, T., Botelho, S. C., Patzke, C., Pak, C., Wernig, M., Sudhof, T. C. <strong>Autism-associated SHANK3 haploinsufficiency causes I(h) channelopathy in human neurons.</strong> Science 352: aaf2669, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26966193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26966193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26966193[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aaf2669" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26966193">Yi et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26966193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Boeckers, T. M., Kreutz, M. R., Winter, C., Zuschratter, W., Smalla, K.-H., Sanmarti-Vila, L., Wex, H., Langnaese, K., Bockmann, J., Garner, C. C., Gundelfinger, E. D. <strong>Proline-rich synapse-associated protein-1/cortactin binding protein 1 (ProSAP1/CortBP1) is a PDZ-domain protein highly enriched in the postsynaptic density.</strong> J. Neurosci. 19: 6506-6518, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10414979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10414979</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10414979[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/10.1523/JNEUROSCI.19-15-06506.1999" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10414979">Boeckers et al. (1999)</a> isolated rat cDNAs encoding Prosap1, a scaffold protein that is highly enriched in the postsynaptic density of excitatory synapses, and a related protein, Prosap2. The Prosap proteins were coexpressed in many regions of the rat brain, but showed a distinct expression pattern in the cerebellum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10414979" 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="Bonaglia, M. C., Giorda, R., Borgatti, R., Felisari, G., Gagliardi, C., Selicorni, A., Zuffardi, O. <strong>Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome.</strong> Am. J. Hum. Genet. 69: 261-268, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11431708[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/10.1086/321293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431708">Bonaglia et al. (2001)</a> predicted that the human PSAP2 (SHANK3) gene encodes a 1,731-amino acid protein. Northern blot analysis indicated that human PSAP2 is expressed primarily in brain as 7- and 8-kb transcripts. In rats and humans, PSAP2 is expressed preferentially in cerebral cortex and cerebellum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431708" 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="#19" class="mim-tip-reference" title="Schuetz, G., Rosario, M., Grimm, J., Boeckers, T. M., Gundelfinger, E. D., Birchmeier, W. <strong>The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cells.</strong> J. Cell Biol. 167: 945-952, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15569713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15569713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15569713[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/10.1083/jcb.200404108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15569713">Schuetz et al. (2004)</a> reported that the 1,806-amino acid mouse Shank3 protein contains 5 N-terminal ankyrin motifs, followed by an SRC (<a href="/entry/190090">190090</a>) homology-3 (SH3) domain, a PDZ domain, a proline-rich region, and a C-terminal sterile-alpha motif (SAM) domain. Immunohistochemical analysis revealed that Shank3 localized to basolateral cell membranes of epithelial tubules of developing mouse kidney at embryonic day 16.5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15569713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Wang, X., McCoy, P. A., Rodriguiz, R. M., Pan, Y., Je, H. S., Roberts, A. C., Kim, C. J., Berrios, J., Colvin, J. S., Bousquet-Moore, D., Lorenzo, I., Wu, G., Weinberg, R. J., Ehlers, M. D., Philpot, B. D., Beaudet, A. L., Wetsel, W. C., Jiang, Y. <strong>Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3.</strong> Hum. Molec. Genet. 20: 3093-3108, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21558424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21558424</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21558424[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddr212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21558424">Wang et al. (2011)</a> found that both mouse and human SHANK3 show extensive alternative splicing and use several promoters. In mouse, the major Shank3 splice variants, Shank3a and Shank3b, initiate from promoters in the upstream region and in intron 2, respectively. Splice variants initiating from 4 additional internal promoters potentially encode N-terminally truncated proteins. <a href="#21" class="mim-tip-reference" title="Wang, X., McCoy, P. A., Rodriguiz, R. M., Pan, Y., Je, H. S., Roberts, A. C., Kim, C. J., Berrios, J., Colvin, J. S., Bousquet-Moore, D., Lorenzo, I., Wu, G., Weinberg, R. J., Ehlers, M. D., Philpot, B. D., Beaudet, A. L., Wetsel, W. C., Jiang, Y. <strong>Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3.</strong> Hum. Molec. Genet. 20: 3093-3108, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21558424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21558424</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21558424[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddr212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21558424">Wang et al. (2011)</a> confirmed at least 11 different Shank3 transcripts in mouse brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21558424" 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="#14" class="mim-tip-reference" title="Mameza, M. G., Dvoretskova, E., Bamann, M., Honck, H.-H., Guler, T., Boeckers, T. M., Schoen, M., Verpelli, C., Sala, C., Barsukov, I., Dityatev, A., Kreienkamp, H.-J. <strong>SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region.</strong> J. Biol. Chem. 288: 26697-26708, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23897824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23897824</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23897824[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M112.424747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23897824">Mameza et al. (2013)</a> stated that all SHANK proteins, including SHANK3, have a conserved N-terminal domain prior to the 6 ankyrin repeats. They called this domain the SHANK/PROSAP N-terminal (SPN) domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23897824" 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 genomic sequence analysis, <a href="#6" class="mim-tip-reference" title="Bonaglia, M. C., Giorda, R., Borgatti, R., Felisari, G., Gagliardi, C., Selicorni, A., Zuffardi, O. <strong>Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome.</strong> Am. J. Hum. Genet. 69: 261-268, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11431708[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/10.1086/321293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431708">Bonaglia et al. (2001)</a> determined that the SHANK3 gene spans 60 kb and contains 22 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The SHANK3 gene contains 24 exons and spans 57 kb (<a href="#9" class="mim-tip-reference" title="Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F., Nygren, G., Rastam, M., Gillberg, I. C., Anckarsater, H., Sponheim, E., Goubran-Botros, H., and 11 others. <strong>Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.</strong> Nature Genet. 39: 25-27, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17173049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17173049</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17173049[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng1933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17173049">Durand et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17173049" 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="Ching, T.-T., Maunakea, A. K., Jun, P., Hong, C., Zardo, G., Pinkel, D., Albertson, D. G., Fridlyand, J., Mao, J.-H., Shchors, K., Weiss, W. A., Costello, J. F. <strong>Epigenome analyses using BAC microarrays identify evolutionary conservation of tissue-specific methylation of SHANK3.</strong> Nature Genet. 37: 645-651, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15895082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15895082</a>] [<a href="https://doi.org/10.1038/ng1563" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15895082">Ching et al. (2005)</a> designed a method using methylation-sensitive restriction enzymes and BAC clone arrays to determine the methylation status of CpG islands genomewide in different tissues with single-nucleotide precision. They identified a CpG island in the SHANK3 gene, the methylation status of which was associated with SHANK3 gene expression. The tissue-specific pattern of CpG island methylation in SHANK3 was similar in human, mouse, and rat tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15895082" 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 investigate the role of intragenic methylation, <a href="#15" class="mim-tip-reference" title="Maunakea, A. K., Nagarajan, R. P., Bilenky, M., Ballinger, T. J., D'Souza, C., Fouse, S. D., Johnson, B. E., Hong, C., Nielsen, C., Zhao, Y., Turecki, G., Delaney, A., and 14 others. <strong>Conserved role of intragenic DNA methylation in regulating alternative promoters.</strong> Nature 466: 253-257, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20613842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20613842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20613842[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20613842">Maunakea et al. (2010)</a> generated a map of DNA methylation from the human brain encompassing 24.7 million of the 28 million CpG sites. From the dense, high-resolution coverage of CpG islands, the majority of methylated CpG islands were shown to be in intragenic and intergenic regions, whereas less than 3% of CpG islands in 5-prime promoters were methylated. The CpG islands in all 3 locations overlapped with RNA markers of transcription initiation, and unmethylated CpG islands also overlapped significantly with trimethylation of histone H3 (see <a href="/entry/602810">602810</a>) lys4, a histone modification enriched at promoters. The general and CpG island-specific patterns of methylation were conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus and its mouse homolog demonstrated that this tissue-specific DNA methylation regulates intragenic promoter activity in vitro and in vivo. These methylation-regulated, alternative transcripts were expressed in a tissue- and cell type-specific manner and were expressed differentially within a single cell type from distinct brain regions. <a href="#15" class="mim-tip-reference" title="Maunakea, A. K., Nagarajan, R. P., Bilenky, M., Ballinger, T. J., D'Souza, C., Fouse, S. D., Johnson, B. E., Hong, C., Nielsen, C., Zhao, Y., Turecki, G., Delaney, A., and 14 others. <strong>Conserved role of intragenic DNA methylation in regulating alternative promoters.</strong> Nature 466: 253-257, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20613842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20613842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20613842[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20613842">Maunakea et al. (2010)</a> concluded that intragenic methylation plays a major role in regulating cell context-specific alternative promoters in gene bodies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20613842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#19" class="mim-tip-reference" title="Schuetz, G., Rosario, M., Grimm, J., Boeckers, T. M., Gundelfinger, E. D., Birchmeier, W. <strong>The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cells.</strong> J. Cell Biol. 167: 945-952, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15569713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15569713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15569713[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/10.1083/jcb.200404108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15569713">Schuetz et al. (2004)</a> stated that the Ret9 isoform of the receptor tyrosine kinase Ret (<a href="/entry/164761">164761</a>), but not the Ret51 isoform, is involved in kidney and enteric nervous system development. Using a 3-dimensional in vitro tubulogenesis assay with MDCK canine kidney cells, they showed that Ret9, but not Ret51, induced epithelial tubule formation and that Shank3 was crucial for Ret9 signaling. Yeast 2-hybrid and coimmunoprecipitation analyses revealed that the PDZ domain of mouse Shank3 interacted with the cytoplasmic domain of Ret9. Shank3 did not interact with Ret51. The proline-rich region of Shank3 interacted with the adaptor protein Grb2 (<a href="/entry/108355">108355</a>), and this interaction was required for sustained ERK/MAPK (see <a href="/entry/176948">176948</a>) and PI3K (see <a href="/entry/171834">171834</a>) signaling downstream of Ret9 and was essential for tubulogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15569713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Shcheglovitov, A., Shcheglovitova, O., Yazawa, M., Portmann, T., Shu, R., Sebastiano, V., Krawisz, A., Froehlich, W., Bernstein, J. A., Hallmayer, J. F., Dolmetsch, R. E. <strong>SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients.</strong> Nature 503: 267-271, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24132240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24132240</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24132240[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24132240">Shcheglovitov et al. (2013)</a> generated induced pluripotent stem (iPS) cells from individuals with Phelan-McDermid syndrome (PHMDS; <a href="/entry/606232">606232</a>) and autism and used them to produce functional neurons. <a href="#20" class="mim-tip-reference" title="Shcheglovitov, A., Shcheglovitova, O., Yazawa, M., Portmann, T., Shu, R., Sebastiano, V., Krawisz, A., Froehlich, W., Bernstein, J. A., Hallmayer, J. F., Dolmetsch, R. E. <strong>SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients.</strong> Nature 503: 267-271, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24132240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24132240</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24132240[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24132240">Shcheglovitov et al. (2013)</a> showed that PHMDS neurons have reduced SHANK3 expression and major defects in excitatory, but not inhibitory, synaptic transmission. Excitatory synaptic transmission in PHMDS neurons could be corrected by restoring SHANK3 expression or by treating neurons with insulin-like growth factor-1 (IGF1; <a href="/entry/147440">147440</a>). IGF1 treatment promoted formation of mature excitatory synapses that lacked SHANK3 but contained PSD95 (<a href="/entry/602887">602887</a>) and NMDA receptors (see <a href="/entry/138249">138249</a>) with fast deactivation kinetics. <a href="#20" class="mim-tip-reference" title="Shcheglovitov, A., Shcheglovitova, O., Yazawa, M., Portmann, T., Shu, R., Sebastiano, V., Krawisz, A., Froehlich, W., Bernstein, J. A., Hallmayer, J. F., Dolmetsch, R. E. <strong>SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients.</strong> Nature 503: 267-271, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24132240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24132240</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24132240[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24132240">Shcheglovitov et al. (2013)</a> concluded that their findings provided direct evidence for a disruption in the ratio of cellular excitation and inhibition in PHMDS neurons, and pointed to a molecular pathway that can be recruited to restore it. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24132240" 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 epitope-tagged domain fragments in protein pull-down assays, <a href="#14" class="mim-tip-reference" title="Mameza, M. G., Dvoretskova, E., Bamann, M., Honck, H.-H., Guler, T., Boeckers, T. M., Schoen, M., Verpelli, C., Sala, C., Barsukov, I., Dityatev, A., Kreienkamp, H.-J. <strong>SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region.</strong> J. Biol. Chem. 288: 26697-26708, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23897824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23897824</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23897824[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M112.424747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23897824">Mameza et al. (2013)</a> showed that the isolated SPN domain of rat Shank3 interacted with the adjacent ankyrin repeat region. This tight intramolecular interaction at the N terminus restricted the availability of the ankyrin repeat region to bind its ligands, Sharpin (<a href="/entry/611885">611885</a>) and alpha-fodrin (SPTAN1; <a href="/entry/182810">182810</a>). Point mutations in rat Shank3 corresponding to autism-related mutations in human SHANK3 did not alter targeting of Shank3 to the plasma membrane in transfected HEK293 cells, but they did alter interaction of Shank3 with Sharpin and alpha-fodrin. RNA interference-mediated knockdown of Shank3 in embryonic mouse hippocampal neurons reduced the frequency of miniature excitatory postsynaptic currents, but not other parameters examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23897824" 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 cellular studies, <a href="#24" class="mim-tip-reference" title="Yi, F., Danko, T., Botelho, S. C., Patzke, C., Pak, C., Wernig, M., Sudhof, T. C. <strong>Autism-associated SHANK3 haploinsufficiency causes I(h) channelopathy in human neurons.</strong> Science 352: aaf2669, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26966193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26966193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26966193[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aaf2669" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26966193">Yi et al. (2016)</a> found that the SHANK3 protein interacts with hyperpolarization-activated cyclic nucleotide-gated cation channels. Introduction of conditional SHANK3 deletions in human embryonic stem cells resulted in modest impairments in dendritic arborization, massive input resistance to increased excitability, and decreases in synaptic transmission. Increased input resistance was consistent with altered cation channel conductance. Hippocampal neurons from heterozygous and homozygous Shank3-mutant mice also showed increased input resistance, reduced hyperpolarization-activated cation channel currents, and increased excitability. <a href="#24" class="mim-tip-reference" title="Yi, F., Danko, T., Botelho, S. C., Patzke, C., Pak, C., Wernig, M., Sudhof, T. C. <strong>Autism-associated SHANK3 haploinsufficiency causes I(h) channelopathy in human neurons.</strong> Science 352: aaf2669, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26966193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26966193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26966193[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aaf2669" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26966193">Yi et al. (2016)</a> hypothesized that these changes may underlie the autistic and cognitive features in patients with SHANK3 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26966193" 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 cultured rat and mouse neurons, <a href="#3" class="mim-tip-reference" title="Bidinosti, M., Botta, P., Kruttner, S., Proenca, C. C., Stoehr, N., Bernhard, M., Fruh, I., Mueller, M., Bonenfant, D., Voshol, H., Carbone, W., Neal, S. J., McTighe, S. M., Roma, G., Dolmetsch, R. E., Porter, J. A., Caroni, P., Bouwmeester, T., Luthi, A., Galimberti, I. <strong>CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency.</strong> Science 351: 1199-1203, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26847545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26847545</a>] [<a href="https://doi.org/10.1126/science.aad5487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26847545">Bidinosti et al. (2016)</a> showed that knockdown of Shank3 resulted in reduced ubiquitination-dependent degradation of the kinase Clk2 (<a href="/entry/602989">602989</a>). Elevated Clk2 levels caused increased phosphorylation and activation of B56-beta (PPP2R5B; <a href="/entry/601644">601644</a>), a regulatory subunit of protein phosphatase-2A (PP2A). Activation of PP2A led to excessive dephosphorylation and deactivation of Akt (see <a href="/entry/164730">164730</a>) and proteins in the mTORC1 pathway (see <a href="/entry/601231">601231</a>). Knockdown of Shank3 also reduced miniature excitatory postsynaptic current frequency in cultured rodent neurons. Human neurons from iPS cells of 2 unrelated PHMDS patients showed reduced AKT phosphorylation and reduced frequency of spontaneous excitatory postsynaptic currents compared with controls. Pharmacologic activation of AKT or inhibition of CLK2 restored AKT phosphorylation and synaptic activity in SHANK3-deficient rodent and human neurons. IGF1 treatment also restored normal dendritic spine density to Shank3-knockdown neurons in an Akt-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26847545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Zhou, Y., Sharma, J., Ke, Q., Landman, R., Yuan, J., Chen, H., Hayden, D. S., Fisher, J. W., III., Jiang, M., Menegas, W., Aida, T., Yan, T., and 23 others. <strong>Atypical behaviour and connectivity in SHANK3-mutant macaques.</strong> Nature 570: 326-331, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31189958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31189958</a>] [<a href="https://doi.org/10.1038/s41586-019-1278-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31189958">Zhou et al. (2019)</a> reported CRISPR-Cas9-mediated generation of germline-transmissible mutations of Shank3 in cynomolgus macaques (Macaca fascicularis) and their F1 offspring. Genotyping of somatic cells as well as brain biopsies confirmed mutations in the Shank3 gene and reduced levels of Shank3 protein in these macaques. Analysis of data from functional magnetic resonance imaging (FMRI) revealed altered local and global connectivity patterns that were indicative of circuit abnormalities. The founder mutants exhibited sleep disturbances, motor deficits, and increased repetitive behaviors, as well as social and learning impairments. <a href="#25" class="mim-tip-reference" title="Zhou, Y., Sharma, J., Ke, Q., Landman, R., Yuan, J., Chen, H., Hayden, D. S., Fisher, J. W., III., Jiang, M., Menegas, W., Aida, T., Yan, T., and 23 others. <strong>Atypical behaviour and connectivity in SHANK3-mutant macaques.</strong> Nature 570: 326-331, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31189958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31189958</a>] [<a href="https://doi.org/10.1038/s41586-019-1278-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31189958">Zhou et al. (2019)</a> concluded that their results paralleled some aspects of the dysfunctions in the SHANK3 gene and circuits, as well as the behavioral phenotypes, that characterize autism spectrum disorder and Phelan-McDermid syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31189958" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Phelan-McDermid Syndrome/Chromosome 22q13.3 Deletion Syndrome</em></strong></p><p>
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SHANK3 is one of the genes disrupted in patients with the 22q13.3 deletion syndrome (<a href="/entry/606232">606232</a>), also known as Phelan-McDermid syndrome. The deletion syndrome is characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, autistic behavior (see <a href="/entry/209850">209850</a>), and minor dysmorphic features (<a href="#9" class="mim-tip-reference" title="Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F., Nygren, G., Rastam, M., Gillberg, I. C., Anckarsater, H., Sponheim, E., Goubran-Botros, H., and 11 others. <strong>Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.</strong> Nature Genet. 39: 25-27, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17173049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17173049</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17173049[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng1933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17173049">Durand et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17173049" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a boy with the 22q13.3 deletion syndrome and severe expressive language delay, <a href="#6" class="mim-tip-reference" title="Bonaglia, M. C., Giorda, R., Borgatti, R., Felisari, G., Gagliardi, C., Selicorni, A., Zuffardi, O. <strong>Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome.</strong> Am. J. Hum. Genet. 69: 261-268, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11431708[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/10.1086/321293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431708">Bonaglia et al. (2001)</a> identified a de novo balanced translocation, t(12;22)(q24.1;q13.3), which disrupted exon 21 of the SHANK3 gene and an intron of the FLJ10659 gene (<a href="/entry/606231">606231</a>). The authors proposed that disruption of the SHANK3 gene was likely responsible for the clinical disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431708" 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="#1" class="mim-tip-reference" title="Anderlid, B.-M., Schoumans, J., Anneren, G., Tapia-Paez, I., Dumanski, J., Blennow, E., Nordenskjold, M. <strong>FISH-mapping of a 100-kb terminal 22q13 deletion.</strong> Hum. Genet. 110: 439-443, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12073014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12073014</a>] [<a href="https://doi.org/10.1007/s00439-002-0713-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12073014">Anderlid et al. (2002)</a> identified an approximately 100-kb deletion in a 33-year-old woman with a submicroscopic 22q13 deletion, mild mental retardation, speech delay, autistic symptoms, and mild facial dysmorphism. The deletion completely encompassed the ACR (<a href="/entry/102480">102480</a>) and RABL2B (<a href="/entry/605413">605413</a>) genes and disrupted SHANK3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12073014" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Wilson, H. L., Wong, A. C. C., Shaw, S. R., Tse, W.-Y., Stapleton, G. A., Phelan, M. C., Hu, S., Marshall, J., McDermid, H. E. <strong>Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms.</strong> J. Med. Genet. 40: 575-584, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12920066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12920066</a>] [<a href="https://doi.org/10.1136/jmg.40.8.575" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12920066">Wilson et al. (2003)</a> determined the deletion size and parent of origin in 56 patients with the 22q13 deletion syndrome. Similar to other terminal deletion syndromes, there was an overabundance of paternal deletions. The deletions varied widely in size, from 130 kb to more than 9 Mb; however, all 45 patients who could be specifically tested for the terminal region showed a deletion of the SHANK3 gene. All patients showed some degree of mental retardation and severe delay or absence of expressive speech, regardless of deletion size. The molecular structure of SHANK3 was further characterized. Because the SHANK3 gene encodes a structural protein of the postsynaptic density, the analysis supported haploinsufficiency of this gene as a major causative factor in the neurologic symptoms of 22q13 deletion syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12920066" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Bonaglia, M. C., Giorda, R., Mani, E., Aceti, G., Anderlid, B.-M., Baroncini, A., Pramparo, T., Zuffardi, O. <strong>Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome. (Letter)</strong> J. Med. Genet. 43: 822-828, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16284256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16284256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16284256[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/10.1136/jmg.2005.038604" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16284256">Bonaglia et al. (2006)</a> studied 2 patients, 1 previously reported by <a href="#1" class="mim-tip-reference" title="Anderlid, B.-M., Schoumans, J., Anneren, G., Tapia-Paez, I., Dumanski, J., Blennow, E., Nordenskjold, M. <strong>FISH-mapping of a 100-kb terminal 22q13 deletion.</strong> Hum. Genet. 110: 439-443, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12073014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12073014</a>] [<a href="https://doi.org/10.1007/s00439-002-0713-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12073014">Anderlid et al. (2002)</a>, with cardinal features of the 22q13.3 deletion syndrome associated with deletion of the last 100 kb of 22q13.3. Both patients showed a breakpoint within the same 15-bp repeat unit in the SHANK3 gene that had previously been identified by <a href="#23" class="mim-tip-reference" title="Wong, A. C. C., Ning, Y., Flint, J., Clark, K., Dumanski, J. P., Ledbetter, D. H., McDermid, H. E. <strong>Molecular characterization of a 130-kb terminal microdeletion at 22q in a child with mild mental retardation.</strong> Am. J. Hum. Genet. 60: 113-120, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981954</a>]" pmid="8981954">Wong et al. (1997)</a> in the patient with 22q13.3 deletion syndrome reported by <a href="#10" class="mim-tip-reference" title="Flint, J., Wilkie, A. O. M., Buckle, V. J., Winter, R. B., Holland, A. J., McDermid, H. E. <strong>The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation.</strong> Nature Genet. 9: 132-139, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719339</a>] [<a href="https://doi.org/10.1038/ng0295-132" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719339">Flint et al. (1995)</a>. <a href="#7" class="mim-tip-reference" title="Bonaglia, M. C., Giorda, R., Mani, E., Aceti, G., Anderlid, B.-M., Baroncini, A., Pramparo, T., Zuffardi, O. <strong>Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome. (Letter)</strong> J. Med. Genet. 43: 822-828, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16284256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16284256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16284256[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/10.1136/jmg.2005.038604" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16284256">Bonaglia et al. (2006)</a> stated that this was the first instance of terminal deletions having a recurrent breakpoint and noted that because the deletion partially overlaps the commercial subtelomeric probe, FISH results are difficult to interpret and similar cases may be overlooked. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12073014+16284256+7719339+8981954" 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="Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F., Nygren, G., Rastam, M., Gillberg, I. C., Anckarsater, H., Sponheim, E., Goubran-Botros, H., and 11 others. <strong>Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.</strong> Nature Genet. 39: 25-27, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17173049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17173049</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17173049[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng1933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17173049">Durand et al. (2007)</a> reported evidence showing that abnormal gene dosage of SHANK3 is associated with severe cognitive deficits, including language and speech disorder and autism spectrum disorder (see <a href="/entry/209850">209850</a>). They identified 3 families with autism spectrum disorder and unambiguous alteration of 22q13 or SHANK3. In the first family, the proband with autism, absent language, and moderate mental retardation carried a de novo deletion of 22q13. The deletion breakpoint was located in intron 8 of SHANK3 and removed 142 kb of the terminal 22q13. In a second family, 2 brothers with severely impaired speech and severe mental retardation were heterozygous for a 1-bp insertion in the SHANK3 gene (<a href="#0001">606230.0001</a>), resulting in a truncated protein. In a third family studied by <a href="#9" class="mim-tip-reference" title="Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F., Nygren, G., Rastam, M., Gillberg, I. C., Anckarsater, H., Sponheim, E., Goubran-Botros, H., and 11 others. <strong>Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.</strong> Nature Genet. 39: 25-27, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17173049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17173049</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17173049[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng1933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17173049">Durand et al. (2007)</a>, a terminal 22q deletion was found in a girl with autism and severe language delay, and a 22qter partial trisomy in her brother with Asperger syndrome who demonstrated precocious language development and fluent speech, but impaired social development. These unbalanced cytogenetic abnormalities were inherited from a paternal translocation, t(14;22)(p11.2;q13.33). The deletion and duplication rearrangement observed in both sibs involved 25 genes, including SHANK3, located in the 800-kb terminal segment of 22q13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17173049" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Moessner, R., Marshall, C. R., Sutcliffe, J. S., Skaug, J., Pinto, D., Vincent, J., Zwaigenbaum, L., Fernandez, B., Roberts, W., Szatmari, P., Scherer, S. W. <strong>Contribution of SHANK3 mutations to autism spectrum disorder.</strong> Am. J. Hum. Genet. 81: 1289-1297, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17999366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17999366</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17999366[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/10.1086/522590" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17999366">Moessner et al. (2007)</a> identified deletions in the SHANK3 gene in 3 (0.75%) of 400 unrelated patients with an autism spectrum disorder. The deletions ranged in size from 277 kb to 4.36 Mb; 1 patient also had a 1.4-Mb duplication at chromosome 20q13.33. The patients were essentially nonverbal and showed poor social interactions and repetitive behaviors. Two had global developmental delay and mild dysmorphic features. A fourth patient with a de novo missense mutation in the SHANK3 gene had autism-like features but had diagnostic scores above the cutoff for autism; she was conceived by in vitro fertilization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17999366" 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 specific screening of the SHANK3 gene in 221 patients with autism spectrum disorders, <a href="#4" class="mim-tip-reference" title="Boccuto, L., Lauri, M., Sarasua, S. M., Skinner, C. D., Buccella, D., Dwivedi, A., Orteschi, D., Collins, J. S., Zollino, M., Visconti, P., DuPont, B., Tiziano, D., Schroer, R. J., Neri, G., Stevenson, R. E., Gurrieri, F., Schwartz, C. E. <strong>Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders.</strong> Europ. J. Hum. Genet. 21: 310-316, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22892527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22892527</a>] [<a href="https://doi.org/10.1038/ejhg.2012.175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22892527">Boccuto et al. (2013)</a> identified 5 (2.3%) index patients with heterozygous changes in that gene (see, e.g., <a href="#0004">606230.0004</a>-<a href="#0006">606230.0006</a>). Three patients had autistic disorder, 1 had pervasive developmental disorder-not otherwise specified (PDD-NOS), and 1 had Asperger syndrome. Most had some additional features including seizures, developmental delay, and mild facial dysmorphism. Screening of this gene in an independent cohort of 104 patients identified 1 (0.9%) with a SHANK3 missense mutation. No cell lines were available from the patients, so functional or expression studies could not be performed. <a href="#4" class="mim-tip-reference" title="Boccuto, L., Lauri, M., Sarasua, S. M., Skinner, C. D., Buccella, D., Dwivedi, A., Orteschi, D., Collins, J. S., Zollino, M., Visconti, P., DuPont, B., Tiziano, D., Schroer, R. J., Neri, G., Stevenson, R. E., Gurrieri, F., Schwartz, C. E. <strong>Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders.</strong> Europ. J. Hum. Genet. 21: 310-316, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22892527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22892527</a>] [<a href="https://doi.org/10.1038/ejhg.2012.175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22892527">Boccuto et al. (2013)</a> also identified a c.1304+48C-T transition (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs76224556;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs76224556</a>) in 17 (7.7%) cases, including 5 with autistic disorder and 12 with PDD-NOS. Four (23.5%) of these patients had an affected sib who also carried the variant. The variant was demonstrated to be inherited from an apparently unaffected parent in 15 cases. However, this variant was significantly more frequent in the patient cohort than in the combined control population (7.7% vs 1.4%, p value less than 0.0002). In the replication cohort, 8 (7.7%) of 104 patients carried the c.1304+48C-T variant. This change occurs in a highly CG-rich region and causes the loss of a CpG dinucleotide, which may affect methylation status. <a href="#4" class="mim-tip-reference" title="Boccuto, L., Lauri, M., Sarasua, S. M., Skinner, C. D., Buccella, D., Dwivedi, A., Orteschi, D., Collins, J. S., Zollino, M., Visconti, P., DuPont, B., Tiziano, D., Schroer, R. J., Neri, G., Stevenson, R. E., Gurrieri, F., Schwartz, C. E. <strong>Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders.</strong> Europ. J. Hum. Genet. 21: 310-316, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22892527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22892527</a>] [<a href="https://doi.org/10.1038/ejhg.2012.175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22892527">Boccuto et al. (2013)</a> concluded that variation in the SHANK3 gene increases the basal susceptibility to autism spectrum disorders, which have a complex etiology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22892527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Schizophrenia</em></strong></p><p>
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<a href="#11" class="mim-tip-reference" title="Gauthier, J., Champagne, N., Lafreniere, R. G., Xiong, L., Spiegelman, D., Brustein, E., Lapointe, M., Peng, H., Cote, M., Noreau, A., Hamdan, F. F., Addington, A. M., and 18 others. <strong>De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.</strong> Proc. Nat. Acad. Sci. 107: 7863-7868, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20385823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20385823</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20385823[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.0906232107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20385823">Gauthier et al. (2010)</a> identified 2 de novo mutations (R1117X, <a href="#0002">606230.0002</a> and R536W, <a href="#0003">606230.0003</a>) in 2 families with schizophrenia (SCZD15; <a href="/entry/613950">613950</a>). One mutation was found in 3 affected brothers, suggesting germline mosaicism, and the other was found in a European woman. In all cases patients also had borderline or mild mental retardation. Zebrafish and rat hippocampal neuron assays revealed behavior and differentiation defects resulting from the R1117X mutation. These mutations were not found in 285 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20385823" 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="#18" class="mim-tip-reference" title="Peca, J., Feliciano, C., Ting, J. T., Wang, W., Wells, M. F., Venkatraman, T. N., Lascola, C. D., Fu, Z., Feng, G. <strong>Shank3 mutant mice display autistic-like behaviours and striatal dysfunction.</strong> Nature 472: 437-442, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21423165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21423165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21423165[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09965" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21423165">Peca et al. (2011)</a> generated mice deficient in Shank3. Shank3B-null mice did not display gross anatomic or histologic brain abnormalities, but on rare occasions exhibited seizures during handling. Spontaneous seizures were never observed. By the age of 3 to 6 months, Shank3B-null mice exhibited self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiologic, and biochemical analyses uncovered defects at striatal synapses and corticostriatal circuits in Shank3 mutant mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21423165" 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="Bangash, M. A., Park, J. M., Melnikova, T., Wang, D., Jeon, S. K., Lee, D., Syeda, S., Kim, J., Kouser, M., Schwartz, J., Cui, Y., Zhao, X., and 10 others. <strong>Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism.</strong> Cell 145: 758-772, 2011. Note: Retraction: Cell 152: 367 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21565394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21565394</a>] [<a href="https://doi.org/10.1016/j.cell.2011.03.052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21565394">Bangash et al. (2011)</a> found that mice heterozygous for expression of a C-terminally truncated Shank3 protein (Shank3 +/delta-C) lacking the Homer-interacting region were born at the expected mendelian ratio, appeared healthy, and grew normally into adulthood. However, Shank3 +/delta-C mice showed deficits in social interactions, with lower levels of social recognition and investigation and episodes of aggression. Shank3 +/delta-C mice displayed normal learning and memory, but they had enhanced locomotor responses to amphetamine and an NMDA agonist, consistent with reduced NMDAR function. Morphologically, synapse structure and number appeared normal; however, electrophysiologic studies showed reduced NMDAR responses in cortical and hippocampal neurons and reduced NMDAR-dependent long-term potentiation and long-term depression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21565394" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Wang, X., McCoy, P. A., Rodriguiz, R. M., Pan, Y., Je, H. S., Roberts, A. C., Kim, C. J., Berrios, J., Colvin, J. S., Bousquet-Moore, D., Lorenzo, I., Wu, G., Weinberg, R. J., Ehlers, M. D., Philpot, B. D., Beaudet, A. L., Wetsel, W. C., Jiang, Y. <strong>Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3.</strong> Hum. Molec. Genet. 20: 3093-3108, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21558424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21558424</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21558424[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddr212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21558424">Wang et al. (2011)</a> developed Shank3(e4-9) mutant mice, which expressed a Shank3 transcript lacking exons 4 through 9. Shank3(e4-9) mice did not express the major Shank3 variants, Shank3a and Shank3b, but they expressed other variants initiated by internal promoters 3, 4, and 5. Shank3(e4-9) mice were obtained at the expected mendelian ratio, and they developed normally and were fertile. However, Shank3(e4-9) mice displayed abnormal social and motor behaviors, aberrant ultrasonic vocalizations, repetitive behaviors, and learning and memory deficits. Dendritic spines of Shank3(e4-9) mice were characterized by subtle morphologic alterations, with abnormal expression of synaptic proteins and receptors, and a deficiency in long-term potentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21558424" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Mei, Y., Monteiro, P., Zhou, Y., Kim, J.-A., Gao, X., Fu, Z., Feng, G. <strong>Adult restoration of Shank3 expression rescues selective autistic-like phenotypes.</strong> Nature 530: 481-484, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26886798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26886798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26886798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature16971" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26886798">Mei et al. (2016)</a> found that conditional knock-in of Shank3 in adult mice, after absence of Shank3 expression during development, restored synaptic levels of postsynaptic proteins comparable to wildtype. This was associated with restoration of postsynaptic excitatory currents, promotion of dendritic spine density, and improvement of certain behavioral abnormalities, including social interaction deficits and repetitive grooming behavior. In contrast, anxiety and motor coordination deficits were not recovered in adulthood. Germline restoration of Shank3 rescued all behavioral phenotypes, and early postnatal restoration of Shank3 also resulted in better phenotypic rescue compared to restoration of expression in adults. The findings were significant in demonstrating that SHANK3 has an effect after development and that there is continued neuronal plasticity in the adult brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26886798" 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="Bidinosti, M., Botta, P., Kruttner, S., Proenca, C. C., Stoehr, N., Bernhard, M., Fruh, I., Mueller, M., Bonenfant, D., Voshol, H., Carbone, W., Neal, S. J., McTighe, S. M., Roma, G., Dolmetsch, R. E., Porter, J. A., Caroni, P., Bouwmeester, T., Luthi, A., Galimberti, I. <strong>CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency.</strong> Science 351: 1199-1203, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26847545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26847545</a>] [<a href="https://doi.org/10.1126/science.aad5487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26847545">Bidinosti et al. (2016)</a> found that neurons from mice lacking expression of major Shank3 isoforms due to ablation of exon 21 had excessive Clk2 protein and activity and reduced Akt phosphorylation in synaptosomal fractions. Pharmacologic inhibition of Clk2 significantly decreased self-grooming and increased normal social behavior in mutant mice and increased Akt phosphorylation in mutant synaptosomal fractions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26847545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>SHANK3 Overexpression</em></strong></p><p>
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<a href="#12" class="mim-tip-reference" title="Han, K., Holder, J. L., Jr., Schaaf, C. P., Lu, H., Chen, H., Kang, H., Tang, J., Wu, Z., Hao, S., Cheung, S. W., Yu, P., Sun, H., Breman, A. M., Patel, A., Lu, H.-C., Zoghbi, H. Y. <strong>SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties.</strong> Nature 503: 72-77, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24153177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24153177</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24153177[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12630" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24153177">Han et al. (2013)</a> developed Shank3 transgenic mice modeling a human SHANK3 duplication and found that they exhibit manic-like behavior and seizures consistent with synaptic excitatory/inhibitory imbalance. The Shank3 transgenic mice showed increased locomotor activity, did not habituate, and were hypersensitive to amphetamine. They also had abnormal circadian rhythms. The mood-stabilizing drug valproate, but not lithium, rescued the manic-like behavior of Shank3 transgenic mice, raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile. <a href="#12" class="mim-tip-reference" title="Han, K., Holder, J. L., Jr., Schaaf, C. P., Lu, H., Chen, H., Kang, H., Tang, J., Wu, Z., Hao, S., Cheung, S. W., Yu, P., Sun, H., Breman, A. M., Patel, A., Lu, H.-C., Zoghbi, H. Y. <strong>SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties.</strong> Nature 503: 72-77, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24153177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24153177</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24153177[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12630" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24153177">Han et al. (2013)</a> also generated a Shank3 in vivo interactome and found that Shank3 directly interacts with the Arp2/3 complex (see <a href="/entry/604221">604221</a>) to increase F-actin levels in Shank3 transgenic mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24153177" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Bangash, M. A., Park, J. M., Melnikova, T., Wang, D., Jeon, S. K., Lee, D., Syeda, S., Kim, J., Kouser, M., Schwartz, J., Cui, Y., Zhao, X., and 10 others. <strong>Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism.</strong> Cell 145: 758-772, 2011. Note: Retraction: Cell 152: 367 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21565394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21565394</a>] [<a href="https://doi.org/10.1016/j.cell.2011.03.052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21565394">Bangash et al. (2011)</a> reported an analysis of a mouse genetic model that deletes the C terminus of Shank3 to mimic human mutations that cause autism spectrum disorder; however, their paper was retracted due to improperly assembled figure panels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21565394" 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"><span class="text-primary">●</span> rs762292772 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs762292772;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs762292772?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs762292772" 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=rs762292772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000004730 OR RCV000190779 OR RCV000366708 OR RCV000754675 OR RCV001374986 OR RCV002503748 OR RCV004734844" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004730, RCV000190779, RCV000366708, RCV000754675, RCV001374986, RCV002503748, RCV004734844" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004730...</a>
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<p>In 2 brothers with severely impaired speech, severe mental retardation, and autistic features consistent with Phelan-McDermid syndrome (PHMDS; <a href="/entry/606232">606232</a>), <a href="#9" class="mim-tip-reference" title="Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F., Nygren, G., Rastam, M., Gillberg, I. C., Anckarsater, H., Sponheim, E., Goubran-Botros, H., and 11 others. <strong>Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.</strong> Nature Genet. 39: 25-27, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17173049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17173049</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17173049[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng1933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17173049">Durand et al. (2007)</a> identified a heterozygous 1-bp insertion (3680insG) in exon 21 of the SHANK3 gene, resulting in a frameshift and premature termination of the protein lacking several crucial domains involved in synaptic targeting and postsynaptic assembly of SHANK3 multimers. Consistent with the loss of these domains, <a href="#9" class="mim-tip-reference" title="Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F., Nygren, G., Rastam, M., Gillberg, I. C., Anckarsater, H., Sponheim, E., Goubran-Botros, H., and 11 others. <strong>Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.</strong> Nature Genet. 39: 25-27, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17173049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17173049</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17173049[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng1933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17173049">Durand et al. (2007)</a> observed no synaptic localization following overexpression of the truncated protein in rat hippocampal neuronal cells compared with the wildtype sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17173049" 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"><span class="text-primary">●</span> rs387906932 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906932;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387906932?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906932" 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=rs387906932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000023519 OR RCV001257625" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023519, RCV001257625" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023519...</a>
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<p>In 3 brothers, 1 with schizoaffective disorder, 2 with schizophrenia, and all 3 with borderline to moderate mental retardation (SCZD15; <a href="/entry/613950">613950</a>), <a href="#11" class="mim-tip-reference" title="Gauthier, J., Champagne, N., Lafreniere, R. G., Xiong, L., Spiegelman, D., Brustein, E., Lapointe, M., Peng, H., Cote, M., Noreau, A., Hamdan, F. F., Addington, A. M., and 18 others. <strong>De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.</strong> Proc. Nat. Acad. Sci. 107: 7863-7868, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20385823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20385823</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20385823[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.0906232107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20385823">Gauthier et al. (2010)</a> identified a de novo heterozygous mutation in the SHANK3 gene, a C-to-T transition resulting in an arg1117-to-ter (R1117X) substitution. The mutation appeared to be of paternal origin based on haplotype analysis and likely due to gonadal mosaicism. The mutation was not found in 285 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20385823" 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"><span class="text-primary">●</span> rs387906933 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906933;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387906933?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906933" 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=rs387906933" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000023520" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023520" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023520</a>
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<p>In a 23-year-old woman of European ancestry diagnosed with schizoaffective disorder at age 11 with a borderline IQ of 73 (SCZD15; <a href="/entry/613950">613950</a>), <a href="#11" class="mim-tip-reference" title="Gauthier, J., Champagne, N., Lafreniere, R. G., Xiong, L., Spiegelman, D., Brustein, E., Lapointe, M., Peng, H., Cote, M., Noreau, A., Hamdan, F. F., Addington, A. M., and 18 others. <strong>De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.</strong> Proc. Nat. Acad. Sci. 107: 7863-7868, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20385823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20385823</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20385823[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.0906232107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20385823">Gauthier et al. (2010)</a> identified a de novo C-to-T transition in the SHANK3 gene, resulting in an arg536-to-trp (R536W) substitution. This mutation was not identified in 285 controls. The mutation was not identified in either parent but parental origin could not be determined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20385823" 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">rs1555910212 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555910212;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=rs1555910212" 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=rs1555910212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000043653" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043653" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043653</a>
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<p>In an Italian boy with pervasive developmental disorder-not otherwise specified (PDD-NOS), severe intellectual disability, seizures, lack of speech, and mild dysmorphic features consistent with Phelan-McDermid syndrome (PHMDS; <a href="/entry/606232">606232</a>), <a href="#4" class="mim-tip-reference" title="Boccuto, L., Lauri, M., Sarasua, S. M., Skinner, C. D., Buccella, D., Dwivedi, A., Orteschi, D., Collins, J. S., Zollino, M., Visconti, P., DuPont, B., Tiziano, D., Schroer, R. J., Neri, G., Stevenson, R. E., Gurrieri, F., Schwartz, C. E. <strong>Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders.</strong> Europ. J. Hum. Genet. 21: 310-316, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22892527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22892527</a>] [<a href="https://doi.org/10.1038/ejhg.2012.175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22892527">Boccuto et al. (2013)</a> identified a heterozygous 1-bp deletion (c.3931delG, NM_001080420.1) in exon 22 of the SHANK3 gene, resulting in a frameshift and premature termination (Glu1311fsTer91), leading to the loss of several domains important for SHANK3 interaction with other proteins. The patient's mother did not carry the mutation, but paternal DNA was not available. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22892527" 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"><span class="text-primary">●</span> rs745950788 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs745950788;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs745950788?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs745950788" 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=rs745950788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000043654 OR RCV000735082 OR RCV001659984" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043654, RCV000735082, RCV001659984" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043654...</a>
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<p>This variant, formerly titled PHELAN-MCDERMID SYNDROME, has been reclassified based on the findings of <a href="#13" class="mim-tip-reference" title="Kolevzon, A., Cai, G., Soorya, L., Takahashi, N., Grodberg, D., Kajiwara, Y., Willner, J. P., Tryfon, A., Buxbaum, J. D. <strong>Analysis of a purported SHANK3 mutation in a boy with autism: clinical impact of rare variant research in neurodevelopmental disabilities.</strong> Brain Res. 1380: 98-105, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21062623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21062623</a>] [<a href="https://doi.org/10.1016/j.brainres.2010.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21062623">Kolevzon et al. (2011)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21062623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 17-year-old Caucasian girl with autistic disorder and speech delay consistent with Phelan-McDermid syndrome (PHMDS; <a href="/entry/606232">606232</a>), <a href="#4" class="mim-tip-reference" title="Boccuto, L., Lauri, M., Sarasua, S. M., Skinner, C. D., Buccella, D., Dwivedi, A., Orteschi, D., Collins, J. S., Zollino, M., Visconti, P., DuPont, B., Tiziano, D., Schroer, R. J., Neri, G., Stevenson, R. E., Gurrieri, F., Schwartz, C. E. <strong>Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders.</strong> Europ. J. Hum. Genet. 21: 310-316, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22892527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22892527</a>] [<a href="https://doi.org/10.1038/ejhg.2012.175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22892527">Boccuto et al. (2013)</a> identified a heterozygous 1-bp insertion in exon 11 of the SHANK3 gene, resulting in a frameshift and premature termination (Ala447fsTer503). The mutation was also found in the father who has learning problems and attention deficit disorder. The patient also had a variant in the NRXN1 gene (<a href="/entry/600565">600565</a>) that was not thought to be pathogenic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22892527" 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="#13" class="mim-tip-reference" title="Kolevzon, A., Cai, G., Soorya, L., Takahashi, N., Grodberg, D., Kajiwara, Y., Willner, J. P., Tryfon, A., Buxbaum, J. D. <strong>Analysis of a purported SHANK3 mutation in a boy with autism: clinical impact of rare variant research in neurodevelopmental disabilities.</strong> Brain Res. 1380: 98-105, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21062623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21062623</a>] [<a href="https://doi.org/10.1016/j.brainres.2010.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21062623">Kolevzon et al. (2011)</a> reported a 7-year-old boy, born to healthy parents of Caucasian ancestry, with autism and intellectual disability. After a commercial laboratory identified the 1-bp insertion (c.1339_1340insG) in exon 11 of SHANK3 as the 'predicted disease-associated mutation,' the authors screened the family for the mutation. They validated the insertion in the boy and also identified it in his mother. Sequencing of the putative exon 11 in 382 controls identified 4 with the G insertion, a rate in controls (approximately 1%) consistent with the mutation being a benign, rare variant. Because the variant would be predicted to disrupt the reference gene, and the penetrance of SHANK3 mutations is high, the authors suggested that the presumptive exon containing the variant is not likely to be present in most or all SHANK3 transcripts. They noted that what is termed exon 11 is absent in the RefSeq Shank3 genes from mouse and rat, and raised concerns about the reported exons 11 and 12 in the human RefSeq SHANK3 sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21062623" 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">rs397514705 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514705;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=rs397514705" 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=rs397514705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000043655 OR RCV001804766" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043655, RCV001804766" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043655...</a>
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<p>In a 25-year-old African-American woman with developmental delay, seizures, mild facial dysmorphism, and autistic disorder consistent with Phelan-McDermid syndrome (PHMDS; <a href="/entry/606232">606232</a>), <a href="#4" class="mim-tip-reference" title="Boccuto, L., Lauri, M., Sarasua, S. M., Skinner, C. D., Buccella, D., Dwivedi, A., Orteschi, D., Collins, J. S., Zollino, M., Visconti, P., DuPont, B., Tiziano, D., Schroer, R. J., Neri, G., Stevenson, R. E., Gurrieri, F., Schwartz, C. E. <strong>Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders.</strong> Europ. J. Hum. Genet. 21: 310-316, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22892527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22892527</a>] [<a href="https://doi.org/10.1038/ejhg.2012.175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22892527">Boccuto et al. (2013)</a> identified a de novo heterozygous 421C-G transversion in exon 4 of the SHANK3 gene, resulting in a pro141-to-ala (P141A) substitution in the N-terminal ankyrin repeats domain. The mutation was not found in several large control databases. This patient also carried a SHANK3 variant (c.1304+48C-T; <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs76224556;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs76224556</a>) that may confer susceptibility to developmental problems. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22892527" 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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Anderlid, B.-M., Schoumans, J., Anneren, G., Tapia-Paez, I., Dumanski, J., Blennow, E., Nordenskjold, M.
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<strong>FISH-mapping of a 100-kb terminal 22q13 deletion.</strong>
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Hum. Genet. 110: 439-443, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12073014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12073014</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12073014" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.cell.2011.03.052" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.aad5487" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/321293" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2005.038604" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1563" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26886798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26886798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26886798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26886798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature16971" target="_blank">Full Text</a>]
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<a id="17" class="mim-anchor"></a>
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<a id="Moessner2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Moessner, R., Marshall, C. R., Sutcliffe, J. S., Skaug, J., Pinto, D., Vincent, J., Zwaigenbaum, L., Fernandez, B., Roberts, W., Szatmari, P., Scherer, S. W.
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<strong>Contribution of SHANK3 mutations to autism spectrum disorder.</strong>
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Am. J. Hum. Genet. 81: 1289-1297, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17999366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17999366</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17999366[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17999366" 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/10.1086/522590" target="_blank">Full Text</a>]
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<a id="18" class="mim-anchor"></a>
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<a id="Peca2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Peca, J., Feliciano, C., Ting, J. T., Wang, W., Wells, M. F., Venkatraman, T. N., Lascola, C. D., Fu, Z., Feng, G.
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<strong>Shank3 mutant mice display autistic-like behaviours and striatal dysfunction.</strong>
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Nature 472: 437-442, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21423165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21423165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21423165[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21423165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature09965" target="_blank">Full Text</a>]
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<a id="19" class="mim-anchor"></a>
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<a id="Schuetz2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Schuetz, G., Rosario, M., Grimm, J., Boeckers, T. M., Gundelfinger, E. D., Birchmeier, W.
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<strong>The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cells.</strong>
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J. Cell Biol. 167: 945-952, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15569713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15569713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15569713[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15569713" 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/10.1083/jcb.200404108" target="_blank">Full Text</a>]
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<a id="Shcheglovitov2013" class="mim-anchor"></a>
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Shcheglovitov, A., Shcheglovitova, O., Yazawa, M., Portmann, T., Shu, R., Sebastiano, V., Krawisz, A., Froehlich, W., Bernstein, J. A., Hallmayer, J. F., Dolmetsch, R. E.
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<strong>SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients.</strong>
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Nature 503: 267-271, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24132240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24132240</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24132240[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24132240" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature12618" target="_blank">Full Text</a>]
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<a id="21" class="mim-anchor"></a>
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<a id="Wang2011" class="mim-anchor"></a>
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Wang, X., McCoy, P. A., Rodriguiz, R. M., Pan, Y., Je, H. S., Roberts, A. C., Kim, C. J., Berrios, J., Colvin, J. S., Bousquet-Moore, D., Lorenzo, I., Wu, G., Weinberg, R. J., Ehlers, M. D., Philpot, B. D., Beaudet, A. L., Wetsel, W. C., Jiang, Y.
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<strong>Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3.</strong>
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Hum. Molec. Genet. 20: 3093-3108, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21558424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21558424</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21558424[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21558424" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddr212" target="_blank">Full Text</a>]
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<a id="Wilson2003" class="mim-anchor"></a>
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Wilson, H. L., Wong, A. C. C., Shaw, S. R., Tse, W.-Y., Stapleton, G. A., Phelan, M. C., Hu, S., Marshall, J., McDermid, H. E.
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<strong>Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms.</strong>
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J. Med. Genet. 40: 575-584, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12920066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12920066</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12920066" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.40.8.575" target="_blank">Full Text</a>]
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<a id="23" class="mim-anchor"></a>
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<a id="Wong1997" class="mim-anchor"></a>
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Wong, A. C. C., Ning, Y., Flint, J., Clark, K., Dumanski, J. P., Ledbetter, D. H., McDermid, H. E.
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<strong>Molecular characterization of a 130-kb terminal microdeletion at 22q in a child with mild mental retardation.</strong>
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Am. J. Hum. Genet. 60: 113-120, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981954</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8981954" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Yi2016" class="mim-anchor"></a>
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Yi, F., Danko, T., Botelho, S. C., Patzke, C., Pak, C., Wernig, M., Sudhof, T. C.
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<strong>Autism-associated SHANK3 haploinsufficiency causes I(h) channelopathy in human neurons.</strong>
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Science 352: aaf2669, 2016. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26966193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26966193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26966193[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26966193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.aaf2669" target="_blank">Full Text</a>]
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<a id="Zhou2019" class="mim-anchor"></a>
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Zhou, Y., Sharma, J., Ke, Q., Landman, R., Yuan, J., Chen, H., Hayden, D. S., Fisher, J. W., III., Jiang, M., Menegas, W., Aida, T., Yan, T., and 23 others.
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<strong>Atypical behaviour and connectivity in SHANK3-mutant macaques.</strong>
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Nature 570: 326-331, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31189958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31189958</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31189958" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41586-019-1278-0" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 01/03/2020
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Carol A. Bocchini - updated : 01/05/2017<br>Patricia A. Hartz - updated : 08/17/2016<br>Cassandra L. Kniffin - updated : 08/08/2016<br>Patricia A. Hartz - updated : 3/10/2014<br>Ada Hamosh - updated : 12/13/2013<br>Ada Hamosh - updated : 11/19/2013<br>Cassandra L. Kniffin - updated : 6/4/2013<br>Patricia A. Hartz - updated : 4/11/2013<br>Patricia A. Hartz - updated : 8/9/2011<br>Ada Hamosh - updated : 6/10/2011<br>Ada Hamosh - updated : 5/3/2011<br>Ada Hamosh - updated : 8/24/2010<br>Cassandra L. Kniffin - updated : 11/26/2007<br>Victor A. McKusick - updated : 2/15/2007<br>Marla J. F. O'Neill - updated : 1/12/2007<br>Victor A. McKusick - updated : 6/1/2005<br>Victor A. McKusick - updated : 10/1/2003
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<span class="mim-text-font">
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Victor A. McKusick : 8/29/2001
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carol : 08/07/2024
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alopez : 03/16/2021<br>carol : 01/07/2020<br>carol : 01/06/2020<br>alopez : 01/03/2020<br>alopez : 03/29/2017<br>alopez : 03/27/2017<br>carol : 01/06/2017<br>carol : 01/05/2017<br>carol : 08/18/2016<br>mgross : 08/17/2016<br>carol : 08/08/2016<br>ckniffin : 08/08/2016<br>mgross : 03/11/2014<br>mcolton : 3/10/2014<br>alopez : 12/13/2013<br>alopez : 11/19/2013<br>carol : 10/1/2013<br>carol : 9/10/2013<br>alopez : 6/10/2013<br>ckniffin : 6/4/2013<br>mgross : 4/11/2013<br>mgross : 4/11/2013<br>mgross : 2/5/2013<br>carol : 3/28/2012<br>mgross : 9/14/2011<br>terry : 8/9/2011<br>alopez : 6/21/2011<br>terry : 6/10/2011<br>terry : 6/10/2011<br>alopez : 5/4/2011<br>terry : 5/3/2011<br>terry : 5/3/2011<br>mgross : 8/30/2010<br>terry : 8/24/2010<br>wwang : 12/12/2007<br>ckniffin : 11/26/2007<br>carol : 3/6/2007<br>ckniffin : 3/5/2007<br>ckniffin : 3/5/2007<br>alopez : 2/20/2007<br>alopez : 2/20/2007<br>joanna : 2/15/2007<br>joanna : 2/15/2007<br>carol : 1/18/2007<br>carol : 1/18/2007<br>terry : 1/12/2007<br>wwang : 6/9/2005<br>wwang : 6/3/2005<br>terry : 6/1/2005<br>tkritzer : 10/3/2003<br>tkritzer : 10/1/2003<br>mgross : 8/30/2001<br>mgross : 8/29/2001
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<strong>*</strong> 606230
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SH3 AND MULTIPLE ANKYRIN REPEAT DOMAINS 3; SHANK3
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PROLINE-RICH SYNAPSE-ASSOCIATED PROTEIN 2; PSAP2<br />
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PROSAP2<br />
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KIAA1650
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SHANK3</em></strong>
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</span>
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</p>
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</div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 699310000;
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<strong>ICD10CM:</strong> Q93.52;
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</span>
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</p>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 22q13.33
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Genomic coordinates <span class="small">(GRCh38)</span> : 22:50,672,823-50,733,212 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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22q13.33
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Schizophrenia 15}
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</span>
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</td>
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<td>
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<span class="mim-font">
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613950
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Phelan-McDermid syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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606232
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The SHANK3 gene encodes a scaffolding protein that is enriched in postsynaptic densities of excitatory synapses (summary by Yi et al., 2016). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Boeckers et al. (1999) isolated rat cDNAs encoding Prosap1, a scaffold protein that is highly enriched in the postsynaptic density of excitatory synapses, and a related protein, Prosap2. The Prosap proteins were coexpressed in many regions of the rat brain, but showed a distinct expression pattern in the cerebellum. </p><p>Bonaglia et al. (2001) predicted that the human PSAP2 (SHANK3) gene encodes a 1,731-amino acid protein. Northern blot analysis indicated that human PSAP2 is expressed primarily in brain as 7- and 8-kb transcripts. In rats and humans, PSAP2 is expressed preferentially in cerebral cortex and cerebellum. </p><p>Schuetz et al. (2004) reported that the 1,806-amino acid mouse Shank3 protein contains 5 N-terminal ankyrin motifs, followed by an SRC (190090) homology-3 (SH3) domain, a PDZ domain, a proline-rich region, and a C-terminal sterile-alpha motif (SAM) domain. Immunohistochemical analysis revealed that Shank3 localized to basolateral cell membranes of epithelial tubules of developing mouse kidney at embryonic day 16.5. </p><p>Wang et al. (2011) found that both mouse and human SHANK3 show extensive alternative splicing and use several promoters. In mouse, the major Shank3 splice variants, Shank3a and Shank3b, initiate from promoters in the upstream region and in intron 2, respectively. Splice variants initiating from 4 additional internal promoters potentially encode N-terminally truncated proteins. Wang et al. (2011) confirmed at least 11 different Shank3 transcripts in mouse brain. </p><p>Mameza et al. (2013) stated that all SHANK proteins, including SHANK3, have a conserved N-terminal domain prior to the 6 ankyrin repeats. They called this domain the SHANK/PROSAP N-terminal (SPN) domain. </p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By genomic sequence analysis, Bonaglia et al. (2001) determined that the SHANK3 gene spans 60 kb and contains 22 exons. </p><p>The SHANK3 gene contains 24 exons and spans 57 kb (Durand et al., 2007). </p><p>Ching et al. (2005) designed a method using methylation-sensitive restriction enzymes and BAC clone arrays to determine the methylation status of CpG islands genomewide in different tissues with single-nucleotide precision. They identified a CpG island in the SHANK3 gene, the methylation status of which was associated with SHANK3 gene expression. The tissue-specific pattern of CpG island methylation in SHANK3 was similar in human, mouse, and rat tissues. </p><p>To investigate the role of intragenic methylation, Maunakea et al. (2010) generated a map of DNA methylation from the human brain encompassing 24.7 million of the 28 million CpG sites. From the dense, high-resolution coverage of CpG islands, the majority of methylated CpG islands were shown to be in intragenic and intergenic regions, whereas less than 3% of CpG islands in 5-prime promoters were methylated. The CpG islands in all 3 locations overlapped with RNA markers of transcription initiation, and unmethylated CpG islands also overlapped significantly with trimethylation of histone H3 (see 602810) lys4, a histone modification enriched at promoters. The general and CpG island-specific patterns of methylation were conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus and its mouse homolog demonstrated that this tissue-specific DNA methylation regulates intragenic promoter activity in vitro and in vivo. These methylation-regulated, alternative transcripts were expressed in a tissue- and cell type-specific manner and were expressed differentially within a single cell type from distinct brain regions. Maunakea et al. (2010) concluded that intragenic methylation plays a major role in regulating cell context-specific alternative promoters in gene bodies. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Schuetz et al. (2004) stated that the Ret9 isoform of the receptor tyrosine kinase Ret (164761), but not the Ret51 isoform, is involved in kidney and enteric nervous system development. Using a 3-dimensional in vitro tubulogenesis assay with MDCK canine kidney cells, they showed that Ret9, but not Ret51, induced epithelial tubule formation and that Shank3 was crucial for Ret9 signaling. Yeast 2-hybrid and coimmunoprecipitation analyses revealed that the PDZ domain of mouse Shank3 interacted with the cytoplasmic domain of Ret9. Shank3 did not interact with Ret51. The proline-rich region of Shank3 interacted with the adaptor protein Grb2 (108355), and this interaction was required for sustained ERK/MAPK (see 176948) and PI3K (see 171834) signaling downstream of Ret9 and was essential for tubulogenesis. </p><p>Shcheglovitov et al. (2013) generated induced pluripotent stem (iPS) cells from individuals with Phelan-McDermid syndrome (PHMDS; 606232) and autism and used them to produce functional neurons. Shcheglovitov et al. (2013) showed that PHMDS neurons have reduced SHANK3 expression and major defects in excitatory, but not inhibitory, synaptic transmission. Excitatory synaptic transmission in PHMDS neurons could be corrected by restoring SHANK3 expression or by treating neurons with insulin-like growth factor-1 (IGF1; 147440). IGF1 treatment promoted formation of mature excitatory synapses that lacked SHANK3 but contained PSD95 (602887) and NMDA receptors (see 138249) with fast deactivation kinetics. Shcheglovitov et al. (2013) concluded that their findings provided direct evidence for a disruption in the ratio of cellular excitation and inhibition in PHMDS neurons, and pointed to a molecular pathway that can be recruited to restore it. </p><p>Using epitope-tagged domain fragments in protein pull-down assays, Mameza et al. (2013) showed that the isolated SPN domain of rat Shank3 interacted with the adjacent ankyrin repeat region. This tight intramolecular interaction at the N terminus restricted the availability of the ankyrin repeat region to bind its ligands, Sharpin (611885) and alpha-fodrin (SPTAN1; 182810). Point mutations in rat Shank3 corresponding to autism-related mutations in human SHANK3 did not alter targeting of Shank3 to the plasma membrane in transfected HEK293 cells, but they did alter interaction of Shank3 with Sharpin and alpha-fodrin. RNA interference-mediated knockdown of Shank3 in embryonic mouse hippocampal neurons reduced the frequency of miniature excitatory postsynaptic currents, but not other parameters examined. </p><p>In cellular studies, Yi et al. (2016) found that the SHANK3 protein interacts with hyperpolarization-activated cyclic nucleotide-gated cation channels. Introduction of conditional SHANK3 deletions in human embryonic stem cells resulted in modest impairments in dendritic arborization, massive input resistance to increased excitability, and decreases in synaptic transmission. Increased input resistance was consistent with altered cation channel conductance. Hippocampal neurons from heterozygous and homozygous Shank3-mutant mice also showed increased input resistance, reduced hyperpolarization-activated cation channel currents, and increased excitability. Yi et al. (2016) hypothesized that these changes may underlie the autistic and cognitive features in patients with SHANK3 mutations. </p><p>Using cultured rat and mouse neurons, Bidinosti et al. (2016) showed that knockdown of Shank3 resulted in reduced ubiquitination-dependent degradation of the kinase Clk2 (602989). Elevated Clk2 levels caused increased phosphorylation and activation of B56-beta (PPP2R5B; 601644), a regulatory subunit of protein phosphatase-2A (PP2A). Activation of PP2A led to excessive dephosphorylation and deactivation of Akt (see 164730) and proteins in the mTORC1 pathway (see 601231). Knockdown of Shank3 also reduced miniature excitatory postsynaptic current frequency in cultured rodent neurons. Human neurons from iPS cells of 2 unrelated PHMDS patients showed reduced AKT phosphorylation and reduced frequency of spontaneous excitatory postsynaptic currents compared with controls. Pharmacologic activation of AKT or inhibition of CLK2 restored AKT phosphorylation and synaptic activity in SHANK3-deficient rodent and human neurons. IGF1 treatment also restored normal dendritic spine density to Shank3-knockdown neurons in an Akt-dependent manner. </p><p>Zhou et al. (2019) reported CRISPR-Cas9-mediated generation of germline-transmissible mutations of Shank3 in cynomolgus macaques (Macaca fascicularis) and their F1 offspring. Genotyping of somatic cells as well as brain biopsies confirmed mutations in the Shank3 gene and reduced levels of Shank3 protein in these macaques. Analysis of data from functional magnetic resonance imaging (FMRI) revealed altered local and global connectivity patterns that were indicative of circuit abnormalities. The founder mutants exhibited sleep disturbances, motor deficits, and increased repetitive behaviors, as well as social and learning impairments. Zhou et al. (2019) concluded that their results paralleled some aspects of the dysfunctions in the SHANK3 gene and circuits, as well as the behavioral phenotypes, that characterize autism spectrum disorder and Phelan-McDermid syndrome. </p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Phelan-McDermid Syndrome/Chromosome 22q13.3 Deletion Syndrome</em></strong></p><p>
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SHANK3 is one of the genes disrupted in patients with the 22q13.3 deletion syndrome (606232), also known as Phelan-McDermid syndrome. The deletion syndrome is characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, autistic behavior (see 209850), and minor dysmorphic features (Durand et al., 2007). </p><p>In a boy with the 22q13.3 deletion syndrome and severe expressive language delay, Bonaglia et al. (2001) identified a de novo balanced translocation, t(12;22)(q24.1;q13.3), which disrupted exon 21 of the SHANK3 gene and an intron of the FLJ10659 gene (606231). The authors proposed that disruption of the SHANK3 gene was likely responsible for the clinical disorder. </p><p>Anderlid et al. (2002) identified an approximately 100-kb deletion in a 33-year-old woman with a submicroscopic 22q13 deletion, mild mental retardation, speech delay, autistic symptoms, and mild facial dysmorphism. The deletion completely encompassed the ACR (102480) and RABL2B (605413) genes and disrupted SHANK3. </p><p>Wilson et al. (2003) determined the deletion size and parent of origin in 56 patients with the 22q13 deletion syndrome. Similar to other terminal deletion syndromes, there was an overabundance of paternal deletions. The deletions varied widely in size, from 130 kb to more than 9 Mb; however, all 45 patients who could be specifically tested for the terminal region showed a deletion of the SHANK3 gene. All patients showed some degree of mental retardation and severe delay or absence of expressive speech, regardless of deletion size. The molecular structure of SHANK3 was further characterized. Because the SHANK3 gene encodes a structural protein of the postsynaptic density, the analysis supported haploinsufficiency of this gene as a major causative factor in the neurologic symptoms of 22q13 deletion syndrome. </p><p>Bonaglia et al. (2006) studied 2 patients, 1 previously reported by Anderlid et al. (2002), with cardinal features of the 22q13.3 deletion syndrome associated with deletion of the last 100 kb of 22q13.3. Both patients showed a breakpoint within the same 15-bp repeat unit in the SHANK3 gene that had previously been identified by Wong et al. (1997) in the patient with 22q13.3 deletion syndrome reported by Flint et al. (1995). Bonaglia et al. (2006) stated that this was the first instance of terminal deletions having a recurrent breakpoint and noted that because the deletion partially overlaps the commercial subtelomeric probe, FISH results are difficult to interpret and similar cases may be overlooked. </p><p>Durand et al. (2007) reported evidence showing that abnormal gene dosage of SHANK3 is associated with severe cognitive deficits, including language and speech disorder and autism spectrum disorder (see 209850). They identified 3 families with autism spectrum disorder and unambiguous alteration of 22q13 or SHANK3. In the first family, the proband with autism, absent language, and moderate mental retardation carried a de novo deletion of 22q13. The deletion breakpoint was located in intron 8 of SHANK3 and removed 142 kb of the terminal 22q13. In a second family, 2 brothers with severely impaired speech and severe mental retardation were heterozygous for a 1-bp insertion in the SHANK3 gene (606230.0001), resulting in a truncated protein. In a third family studied by Durand et al. (2007), a terminal 22q deletion was found in a girl with autism and severe language delay, and a 22qter partial trisomy in her brother with Asperger syndrome who demonstrated precocious language development and fluent speech, but impaired social development. These unbalanced cytogenetic abnormalities were inherited from a paternal translocation, t(14;22)(p11.2;q13.33). The deletion and duplication rearrangement observed in both sibs involved 25 genes, including SHANK3, located in the 800-kb terminal segment of 22q13. </p><p>Moessner et al. (2007) identified deletions in the SHANK3 gene in 3 (0.75%) of 400 unrelated patients with an autism spectrum disorder. The deletions ranged in size from 277 kb to 4.36 Mb; 1 patient also had a 1.4-Mb duplication at chromosome 20q13.33. The patients were essentially nonverbal and showed poor social interactions and repetitive behaviors. Two had global developmental delay and mild dysmorphic features. A fourth patient with a de novo missense mutation in the SHANK3 gene had autism-like features but had diagnostic scores above the cutoff for autism; she was conceived by in vitro fertilization. </p><p>By specific screening of the SHANK3 gene in 221 patients with autism spectrum disorders, Boccuto et al. (2013) identified 5 (2.3%) index patients with heterozygous changes in that gene (see, e.g., 606230.0004-606230.0006). Three patients had autistic disorder, 1 had pervasive developmental disorder-not otherwise specified (PDD-NOS), and 1 had Asperger syndrome. Most had some additional features including seizures, developmental delay, and mild facial dysmorphism. Screening of this gene in an independent cohort of 104 patients identified 1 (0.9%) with a SHANK3 missense mutation. No cell lines were available from the patients, so functional or expression studies could not be performed. Boccuto et al. (2013) also identified a c.1304+48C-T transition (rs76224556) in 17 (7.7%) cases, including 5 with autistic disorder and 12 with PDD-NOS. Four (23.5%) of these patients had an affected sib who also carried the variant. The variant was demonstrated to be inherited from an apparently unaffected parent in 15 cases. However, this variant was significantly more frequent in the patient cohort than in the combined control population (7.7% vs 1.4%, p value less than 0.0002). In the replication cohort, 8 (7.7%) of 104 patients carried the c.1304+48C-T variant. This change occurs in a highly CG-rich region and causes the loss of a CpG dinucleotide, which may affect methylation status. Boccuto et al. (2013) concluded that variation in the SHANK3 gene increases the basal susceptibility to autism spectrum disorders, which have a complex etiology. </p><p><strong><em>Schizophrenia</em></strong></p><p>
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Gauthier et al. (2010) identified 2 de novo mutations (R1117X, 606230.0002 and R536W, 606230.0003) in 2 families with schizophrenia (SCZD15; 613950). One mutation was found in 3 affected brothers, suggesting germline mosaicism, and the other was found in a European woman. In all cases patients also had borderline or mild mental retardation. Zebrafish and rat hippocampal neuron assays revealed behavior and differentiation defects resulting from the R1117X mutation. These mutations were not found in 285 controls. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Peca et al. (2011) generated mice deficient in Shank3. Shank3B-null mice did not display gross anatomic or histologic brain abnormalities, but on rare occasions exhibited seizures during handling. Spontaneous seizures were never observed. By the age of 3 to 6 months, Shank3B-null mice exhibited self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiologic, and biochemical analyses uncovered defects at striatal synapses and corticostriatal circuits in Shank3 mutant mice. </p><p>Bangash et al. (2011) found that mice heterozygous for expression of a C-terminally truncated Shank3 protein (Shank3 +/delta-C) lacking the Homer-interacting region were born at the expected mendelian ratio, appeared healthy, and grew normally into adulthood. However, Shank3 +/delta-C mice showed deficits in social interactions, with lower levels of social recognition and investigation and episodes of aggression. Shank3 +/delta-C mice displayed normal learning and memory, but they had enhanced locomotor responses to amphetamine and an NMDA agonist, consistent with reduced NMDAR function. Morphologically, synapse structure and number appeared normal; however, electrophysiologic studies showed reduced NMDAR responses in cortical and hippocampal neurons and reduced NMDAR-dependent long-term potentiation and long-term depression. </p><p>Wang et al. (2011) developed Shank3(e4-9) mutant mice, which expressed a Shank3 transcript lacking exons 4 through 9. Shank3(e4-9) mice did not express the major Shank3 variants, Shank3a and Shank3b, but they expressed other variants initiated by internal promoters 3, 4, and 5. Shank3(e4-9) mice were obtained at the expected mendelian ratio, and they developed normally and were fertile. However, Shank3(e4-9) mice displayed abnormal social and motor behaviors, aberrant ultrasonic vocalizations, repetitive behaviors, and learning and memory deficits. Dendritic spines of Shank3(e4-9) mice were characterized by subtle morphologic alterations, with abnormal expression of synaptic proteins and receptors, and a deficiency in long-term potentiation. </p><p>Mei et al. (2016) found that conditional knock-in of Shank3 in adult mice, after absence of Shank3 expression during development, restored synaptic levels of postsynaptic proteins comparable to wildtype. This was associated with restoration of postsynaptic excitatory currents, promotion of dendritic spine density, and improvement of certain behavioral abnormalities, including social interaction deficits and repetitive grooming behavior. In contrast, anxiety and motor coordination deficits were not recovered in adulthood. Germline restoration of Shank3 rescued all behavioral phenotypes, and early postnatal restoration of Shank3 also resulted in better phenotypic rescue compared to restoration of expression in adults. The findings were significant in demonstrating that SHANK3 has an effect after development and that there is continued neuronal plasticity in the adult brain. </p><p>Bidinosti et al. (2016) found that neurons from mice lacking expression of major Shank3 isoforms due to ablation of exon 21 had excessive Clk2 protein and activity and reduced Akt phosphorylation in synaptosomal fractions. Pharmacologic inhibition of Clk2 significantly decreased self-grooming and increased normal social behavior in mutant mice and increased Akt phosphorylation in mutant synaptosomal fractions. </p><p><strong><em>SHANK3 Overexpression</em></strong></p><p>
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Han et al. (2013) developed Shank3 transgenic mice modeling a human SHANK3 duplication and found that they exhibit manic-like behavior and seizures consistent with synaptic excitatory/inhibitory imbalance. The Shank3 transgenic mice showed increased locomotor activity, did not habituate, and were hypersensitive to amphetamine. They also had abnormal circadian rhythms. The mood-stabilizing drug valproate, but not lithium, rescued the manic-like behavior of Shank3 transgenic mice, raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile. Han et al. (2013) also generated a Shank3 in vivo interactome and found that Shank3 directly interacts with the Arp2/3 complex (see 604221) to increase F-actin levels in Shank3 transgenic mice. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Bangash et al. (2011) reported an analysis of a mouse genetic model that deletes the C terminus of Shank3 to mimic human mutations that cause autism spectrum disorder; however, their paper was retracted due to improperly assembled figure panels. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>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 PHELAN-MCDERMID SYNDROME</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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SHANK3, 1-BP INS, 3680G
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<br />
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SNP: rs762292772,
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gnomAD: rs762292772,
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ClinVar: RCV000004730, RCV000190779, RCV000366708, RCV000754675, RCV001374986, RCV002503748, RCV004734844
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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 2 brothers with severely impaired speech, severe mental retardation, and autistic features consistent with Phelan-McDermid syndrome (PHMDS; 606232), Durand et al. (2007) identified a heterozygous 1-bp insertion (3680insG) in exon 21 of the SHANK3 gene, resulting in a frameshift and premature termination of the protein lacking several crucial domains involved in synaptic targeting and postsynaptic assembly of SHANK3 multimers. Consistent with the loss of these domains, Durand et al. (2007) observed no synaptic localization following overexpression of the truncated protein in rat hippocampal neuronal cells compared with the wildtype sequence. </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 SCHIZOPHRENIA 15</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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SHANK3, ARG1117TER
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<br />
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SNP: rs387906932,
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gnomAD: rs387906932,
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ClinVar: RCV000023519, RCV001257625
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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 3 brothers, 1 with schizoaffective disorder, 2 with schizophrenia, and all 3 with borderline to moderate mental retardation (SCZD15; 613950), Gauthier et al. (2010) identified a de novo heterozygous mutation in the SHANK3 gene, a C-to-T transition resulting in an arg1117-to-ter (R1117X) substitution. The mutation appeared to be of paternal origin based on haplotype analysis and likely due to gonadal mosaicism. The mutation was not found in 285 controls. </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 SCHIZOPHRENIA 15</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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SHANK3, ARG536TRP
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<br />
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SNP: rs387906933,
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gnomAD: rs387906933,
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ClinVar: RCV000023520
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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 23-year-old woman of European ancestry diagnosed with schizoaffective disorder at age 11 with a borderline IQ of 73 (SCZD15; 613950), Gauthier et al. (2010) identified a de novo C-to-T transition in the SHANK3 gene, resulting in an arg536-to-trp (R536W) substitution. This mutation was not identified in 285 controls. The mutation was not identified in either parent but parental origin could not be determined. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0004 PHELAN-MCDERMID SYNDROME</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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SHANK3, 1-BP DEL, 3931G
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<br />
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SNP: rs1555910212,
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ClinVar: RCV000043653
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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 an Italian boy with pervasive developmental disorder-not otherwise specified (PDD-NOS), severe intellectual disability, seizures, lack of speech, and mild dysmorphic features consistent with Phelan-McDermid syndrome (PHMDS; 606232), Boccuto et al. (2013) identified a heterozygous 1-bp deletion (c.3931delG, NM_001080420.1) in exon 22 of the SHANK3 gene, resulting in a frameshift and premature termination (Glu1311fsTer91), leading to the loss of several domains important for SHANK3 interaction with other proteins. The patient's mother did not carry the mutation, but paternal DNA was not available. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0005 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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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SHANK3, 1-BP INS, 1339G
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<br />
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SNP: rs745950788,
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gnomAD: rs745950788,
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ClinVar: RCV000043654, RCV000735082, RCV001659984
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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>This variant, formerly titled PHELAN-MCDERMID SYNDROME, has been reclassified based on the findings of Kolevzon et al. (2011). </p><p>In a 17-year-old Caucasian girl with autistic disorder and speech delay consistent with Phelan-McDermid syndrome (PHMDS; 606232), Boccuto et al. (2013) identified a heterozygous 1-bp insertion in exon 11 of the SHANK3 gene, resulting in a frameshift and premature termination (Ala447fsTer503). The mutation was also found in the father who has learning problems and attention deficit disorder. The patient also had a variant in the NRXN1 gene (600565) that was not thought to be pathogenic. </p><p>Kolevzon et al. (2011) reported a 7-year-old boy, born to healthy parents of Caucasian ancestry, with autism and intellectual disability. After a commercial laboratory identified the 1-bp insertion (c.1339_1340insG) in exon 11 of SHANK3 as the 'predicted disease-associated mutation,' the authors screened the family for the mutation. They validated the insertion in the boy and also identified it in his mother. Sequencing of the putative exon 11 in 382 controls identified 4 with the G insertion, a rate in controls (approximately 1%) consistent with the mutation being a benign, rare variant. Because the variant would be predicted to disrupt the reference gene, and the penetrance of SHANK3 mutations is high, the authors suggested that the presumptive exon containing the variant is not likely to be present in most or all SHANK3 transcripts. They noted that what is termed exon 11 is absent in the RefSeq Shank3 genes from mouse and rat, and raised concerns about the reported exons 11 and 12 in the human RefSeq SHANK3 sequence. </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>
|
|
<span class="mim-font">
|
|
<strong>.0006 PHELAN-MCDERMID SYNDROME</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
SHANK3, PRO141ALA
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<br />
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SNP: rs397514705,
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|
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ClinVar: RCV000043655, RCV001804766
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|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 25-year-old African-American woman with developmental delay, seizures, mild facial dysmorphism, and autistic disorder consistent with Phelan-McDermid syndrome (PHMDS; 606232), Boccuto et al. (2013) identified a de novo heterozygous 421C-G transversion in exon 4 of the SHANK3 gene, resulting in a pro141-to-ala (P141A) substitution in the N-terminal ankyrin repeats domain. The mutation was not found in several large control databases. This patient also carried a SHANK3 variant (c.1304+48C-T; rs76224556) that may confer susceptibility to developmental problems. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
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</h4>
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<div>
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<p />
|
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Anderlid, B.-M., Schoumans, J., Anneren, G., Tapia-Paez, I., Dumanski, J., Blennow, E., Nordenskjold, M.
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<strong>FISH-mapping of a 100-kb terminal 22q13 deletion.</strong>
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|
Hum. Genet. 110: 439-443, 2002.
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<li>
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<p class="mim-text-font">
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Bangash, M. A., Park, J. M., Melnikova, T., Wang, D., Jeon, S. K., Lee, D., Syeda, S., Kim, J., Kouser, M., Schwartz, J., Cui, Y., Zhao, X., and 10 others.
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|
<strong>Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism.</strong>
|
|
Cell 145: 758-772, 2011. Note: Retraction: Cell 152: 367 only, 2013.
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<p class="mim-text-font">
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Bidinosti, M., Botta, P., Kruttner, S., Proenca, C. C., Stoehr, N., Bernhard, M., Fruh, I., Mueller, M., Bonenfant, D., Voshol, H., Carbone, W., Neal, S. J., McTighe, S. M., Roma, G., Dolmetsch, R. E., Porter, J. A., Caroni, P., Bouwmeester, T., Luthi, A., Galimberti, I.
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|
<strong>CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency.</strong>
|
|
Science 351: 1199-1203, 2016.
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[PubMed: 26847545]
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[Full Text: https://doi.org/10.1126/science.aad5487]
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<p class="mim-text-font">
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Boccuto, L., Lauri, M., Sarasua, S. M., Skinner, C. D., Buccella, D., Dwivedi, A., Orteschi, D., Collins, J. S., Zollino, M., Visconti, P., DuPont, B., Tiziano, D., Schroer, R. J., Neri, G., Stevenson, R. E., Gurrieri, F., Schwartz, C. E.
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<strong>Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders.</strong>
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Europ. J. Hum. Genet. 21: 310-316, 2013.
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[PubMed: 22892527]
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[Full Text: https://doi.org/10.1038/ejhg.2012.175]
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<p class="mim-text-font">
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Boeckers, T. M., Kreutz, M. R., Winter, C., Zuschratter, W., Smalla, K.-H., Sanmarti-Vila, L., Wex, H., Langnaese, K., Bockmann, J., Garner, C. C., Gundelfinger, E. D.
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<strong>Proline-rich synapse-associated protein-1/cortactin binding protein 1 (ProSAP1/CortBP1) is a PDZ-domain protein highly enriched in the postsynaptic density.</strong>
|
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J. Neurosci. 19: 6506-6518, 1999.
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[PubMed: 10414979]
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[Full Text: https://doi.org/10.1523/JNEUROSCI.19-15-06506.1999]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Bonaglia, M. C., Giorda, R., Borgatti, R., Felisari, G., Gagliardi, C., Selicorni, A., Zuffardi, O.
|
|
<strong>Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome.</strong>
|
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Am. J. Hum. Genet. 69: 261-268, 2001.
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[PubMed: 11431708]
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[Full Text: https://doi.org/10.1086/321293]
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</p>
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<li>
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<p class="mim-text-font">
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Bonaglia, M. C., Giorda, R., Mani, E., Aceti, G., Anderlid, B.-M., Baroncini, A., Pramparo, T., Zuffardi, O.
|
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<strong>Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome. (Letter)</strong>
|
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J. Med. Genet. 43: 822-828, 2006.
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[PubMed: 16284256]
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[Full Text: https://doi.org/10.1136/jmg.2005.038604]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Ching, T.-T., Maunakea, A. K., Jun, P., Hong, C., Zardo, G., Pinkel, D., Albertson, D. G., Fridlyand, J., Mao, J.-H., Shchors, K., Weiss, W. A., Costello, J. F.
|
|
<strong>Epigenome analyses using BAC microarrays identify evolutionary conservation of tissue-specific methylation of SHANK3.</strong>
|
|
Nature Genet. 37: 645-651, 2005.
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|
|
[PubMed: 15895082]
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[Full Text: https://doi.org/10.1038/ng1563]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F., Nygren, G., Rastam, M., Gillberg, I. C., Anckarsater, H., Sponheim, E., Goubran-Botros, H., and 11 others.
|
|
<strong>Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.</strong>
|
|
Nature Genet. 39: 25-27, 2007.
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[PubMed: 17173049]
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[Full Text: https://doi.org/10.1038/ng1933]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Flint, J., Wilkie, A. O. M., Buckle, V. J., Winter, R. B., Holland, A. J., McDermid, H. E.
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<strong>The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation.</strong>
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Nature Genet. 9: 132-139, 1995.
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[PubMed: 7719339]
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[Full Text: https://doi.org/10.1038/ng0295-132]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Gauthier, J., Champagne, N., Lafreniere, R. G., Xiong, L., Spiegelman, D., Brustein, E., Lapointe, M., Peng, H., Cote, M., Noreau, A., Hamdan, F. F., Addington, A. M., and 18 others.
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<strong>De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.</strong>
|
|
Proc. Nat. Acad. Sci. 107: 7863-7868, 2010.
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[PubMed: 20385823]
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[Full Text: https://doi.org/10.1073/pnas.0906232107]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Han, K., Holder, J. L., Jr., Schaaf, C. P., Lu, H., Chen, H., Kang, H., Tang, J., Wu, Z., Hao, S., Cheung, S. W., Yu, P., Sun, H., Breman, A. M., Patel, A., Lu, H.-C., Zoghbi, H. Y.
|
|
<strong>SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties.</strong>
|
|
Nature 503: 72-77, 2013.
|
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|
[PubMed: 24153177]
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[Full Text: https://doi.org/10.1038/nature12630]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kolevzon, A., Cai, G., Soorya, L., Takahashi, N., Grodberg, D., Kajiwara, Y., Willner, J. P., Tryfon, A., Buxbaum, J. D.
|
|
<strong>Analysis of a purported SHANK3 mutation in a boy with autism: clinical impact of rare variant research in neurodevelopmental disabilities.</strong>
|
|
Brain Res. 1380: 98-105, 2011.
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[PubMed: 21062623]
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[Full Text: https://doi.org/10.1016/j.brainres.2010.11.005]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Mameza, M. G., Dvoretskova, E., Bamann, M., Honck, H.-H., Guler, T., Boeckers, T. M., Schoen, M., Verpelli, C., Sala, C., Barsukov, I., Dityatev, A., Kreienkamp, H.-J.
|
|
<strong>SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region.</strong>
|
|
J. Biol. Chem. 288: 26697-26708, 2013.
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[PubMed: 23897824]
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[Full Text: https://doi.org/10.1074/jbc.M112.424747]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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