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Entry
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- *602926 - SYNTAXIN-BINDING PROTEIN 1; STXBP1
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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">*602926</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="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<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="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602926">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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</div>
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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=ENSG00000136854;t=ENST00000373299" 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=6812" 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=602926" 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 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=ENSG00000136854;t=ENST00000373299" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001032221,NM_001374306,NM_001374307,NM_001374308,NM_001374309,NM_001374310,NM_001374311,NM_001374312,NM_001374313,NM_001374314,NM_001374315,NM_003165" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001032221" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=602926" 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=04235&isoform_id=04235_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/STXBP1" 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/1944340,3041873,3041875,4507297,16041740,50403646,51476961,62087940,73760415,119608085,119608087,221039756,221040632,221041026,1746322642,1746322644,1746322650,1746322654,1746322666,1746322685,1746322687,1746322689,1746322695,1746322706" 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/P61764" 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=6812" 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=ENSG00000136854;t=ENST00000373299" 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=STXBP1" 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=STXBP1" 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+6812" 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/STXBP1" 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:6812" 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/6812" 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=chr9&hgg_gene=ENST00000373302.8&hgg_start=127611912&hgg_end=127696029&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:11444" 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:11444" 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/stxbp1" 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=602926[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=602926[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/STXBP1/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/ENSG00000136854" 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=STXBP1" 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=STXBP1" 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=STXBP1" 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=STXBP1&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/PA36241" 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:11444" 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/FBgn0004574.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:107363" 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/STXBP1#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:107363" 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/6812/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/OMIA002537/" 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=6812" 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=WBGene00006757;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-050626-106" 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:6812" 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=STXBP1&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> 768666006<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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602926
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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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SYNTAXIN-BINDING PROTEIN 1; STXBP1
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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">
|
|
UNC18, C. ELEGANS, HOMOLOG OF, 1<br />
|
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MUNC18-1
|
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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">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=STXBP1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">STXBP1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/9/518?start=-3&limit=10&highlight=518">9q34.11</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:127611912-127696029&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'})">9:127,611,912-127,696,029</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>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<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">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<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>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
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</thead>
|
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<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/9/518?start=-3&limit=10&highlight=518">
|
|
9q34.11
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Developmental and epileptic encephalopathy 4
|
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|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/612164"> 612164 </a>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
</span>
|
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</td>
|
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>Within the secretory pathway, proteins and other cargo are transferred from one compartment to another by vesicular traffic. Transport vesicles bud from donor membranes and dock to specific acceptor compartments. The S. cerevisiae protein Sec1 participates in the constitutive secretory pathway between the Golgi apparatus and the plasma membrane. <a href="#10" class="mim-tip-reference" title="Pevsner, J., Hsu, S.-C., Scheller, R. H. <strong>n-Sec1: a neural-specific syntaxin-binding protein.</strong> Proc. Nat. Acad. Sci. 91: 1445-1449, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8108429/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8108429</a>] [<a href="https://doi.org/10.1073/pnas.91.4.1445" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8108429">Pevsner et al. (1994)</a> identified rat Stxbp1, which they called n-Sec1. The predicted 68-kD n-Sec1 protein shares 27% identity with S. cerevisiae Sec1 and 59% identity with C. elegans Unc18. RNA blot analysis showed that n-Sec1 mRNA expression was neural-specific. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8108429" 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>Since Unc18 mutation leads to severe paralysis and presynaptic acetylcholine accumulation, Unc18 has been implicated in neurotransmitter release. <a href="#3" class="mim-tip-reference" title="Gengyo-Ando, K., Kitayama, H., Mukaida, M., Ikawa, Y. <strong>A murine neural-specific homolog corrects cholinergic defects in Caenorhabditis elegans unc-18 mutants.</strong> J. Neurosci. 16: 6695-6702, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8824310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8824310</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=8824310[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.16-21-06695.1996" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8824310">Gengyo-Ando et al. (1996)</a> identified cDNAs encoding 2 mouse Unc18 homologs, a neural-specific protein called Munc18-1 and a ubiquitous protein called Munc18-3. They used the murine cDNAs to isolate human Munc18-1 cDNAs from a fetal brain cDNA library. The sequences of the predicted 594-amino acid mouse and human Munc18-1 proteins are identical. <a href="#3" class="mim-tip-reference" title="Gengyo-Ando, K., Kitayama, H., Mukaida, M., Ikawa, Y. <strong>A murine neural-specific homolog corrects cholinergic defects in Caenorhabditis elegans unc-18 mutants.</strong> J. Neurosci. 16: 6695-6702, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8824310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8824310</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=8824310[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.16-21-06695.1996" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8824310">Gengyo-Ando et al. (1996)</a> found that Munc18-1 complemented the locomotion and cholinergic defects in Unc18 mutant animals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8824310" 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 Northern blot analysis of human tissues, <a href="#14" class="mim-tip-reference" title="Swanson, D. A., Steel, J. M., Valle, D. <strong>Identification and characterization of the human ortholog of rat STXBP1, a protein implicated in vesicle trafficking and neurotransmitter release.</strong> Genomics 48: 373-376, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9545644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9545644</a>] [<a href="https://doi.org/10.1006/geno.1997.5202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9545644">Swanson et al. (1998)</a> determined that STXBP1 is expressed as a 4-kb transcript in various tissues. The highest levels of expression were observed in retina and cerebellum. RT-PCR analysis revealed an additional, alternatively spliced form of STXBP1 in retina and cerebellum. This mRNA contains an additional exon and encodes a predicted 603-amino acid protein. Two alternatively spliced forms of STXBP1 are also found in rat, and the predicted proteins are identical to their human counterparts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9545644" 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="#6" class="mim-tip-reference" title="Hamdan, F. F., Piton, A., Gauthier, J., Lortie, A., Dubeau, F., Dobrzeniecka, S., Spiegelman, D., Noreau, A., Pellerin, S., Cote, M., Henrion, E., Fombonne, E., Mottron, L., Marineau, C., Drapeau, P., Lafreniere, R. G., Lacaille, J. C., Rouleau, G. A., Michaud, J. L. <strong>De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy.</strong> Ann. Neurol. 65: 748-753, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19557857/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19557857</a>] [<a href="https://doi.org/10.1002/ana.21625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19557857">Hamdan et al. (2009)</a> stated that the STXBP1 gene contains 20 exons and that alternative splicing results in 2 isoforms with and without exon 19. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19557857" 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 fluorescence in situ hybridization, <a href="#14" class="mim-tip-reference" title="Swanson, D. A., Steel, J. M., Valle, D. <strong>Identification and characterization of the human ortholog of rat STXBP1, a protein implicated in vesicle trafficking and neurotransmitter release.</strong> Genomics 48: 373-376, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9545644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9545644</a>] [<a href="https://doi.org/10.1006/geno.1997.5202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9545644">Swanson et al. (1998)</a> mapped the STXBP1 gene to chromosome 9q34.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9545644" 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="#10" class="mim-tip-reference" title="Pevsner, J., Hsu, S.-C., Scheller, R. H. <strong>n-Sec1: a neural-specific syntaxin-binding protein.</strong> Proc. Nat. Acad. Sci. 91: 1445-1449, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8108429/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8108429</a>] [<a href="https://doi.org/10.1073/pnas.91.4.1445" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8108429">Pevsner et al. (1994)</a> found that rat n-Sec1 is a neural-specific, syntaxin (see <a href="/entry/186590">186590</a>)-binding protein that may participate in the regulation of synaptic vesicle docking and fusion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8108429" 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="Yang, R., Puranam, R. S., Butler, L. S., Qian, W.-H., He, X.-P., Moyer, M. B., Blackburn, K., Andrews, P. I., McNamara, J. O. <strong>Autoimmunity to Munc-18 in Rasmussen's encephalitis.</strong> Neuron 28: 375-383, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11144349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11144349</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)00118-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11144349">Yang et al. (2000)</a> identified high titer autoantibodies against Munc18 in the serum and CSF of a single patient with Rasmussen encephalitis, a rare disorder characterized by progressive degeneration of a single cerebral hemisphere and intractable seizures. The patient had previously been reported by <a href="#11" class="mim-tip-reference" title="Rogers, S. W., Andrews, P. I., Gahring, L. C., Whisenand, T., Cauley, K., Crain, B., Hughes, T. E., Heinemann, S. F., McNamara, J. O. <strong>Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis.</strong> Science 265: 648-651, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8036512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8036512</a>] [<a href="https://doi.org/10.1126/science.8036512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8036512">Rogers et al. (1994)</a> who identified autoantibodies against GLUR3 (GRIA3; <a href="/entry/305915">305915</a>) in serum and CSF. Weak immunoreactivity to Munc18 was found in 3 of 14 additional patients with Rasmussen encephalitis, but often only on prolonged exposure or multiple experiments. As Munc18 is a cytosolic protein, <a href="#20" class="mim-tip-reference" title="Yang, R., Puranam, R. S., Butler, L. S., Qian, W.-H., He, X.-P., Moyer, M. B., Blackburn, K., Andrews, P. I., McNamara, J. O. <strong>Autoimmunity to Munc-18 in Rasmussen's encephalitis.</strong> Neuron 28: 375-383, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11144349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11144349</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)00118-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11144349">Yang et al. (2000)</a> hypothesized that humoral attack on GluR3 would first damage neurons, thus exposing Munc18 and leading to expanded immune attack. Both proteins are involved in synaptic transmission; immune attack on these proteins may have acted synergistically to produce a severe neurologic phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8036512+11144349" 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 adrenal chromaffin cells, <a href="#2" class="mim-tip-reference" title="Fisher, R. J., Pevsner, J., Burgoyne, R. D. <strong>Control of fusion pore dynamics during exocytosis by Munc18.</strong> Science 291: 875-878, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11157167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11157167</a>] [<a href="https://doi.org/10.1126/science.291.5505.875" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11157167">Fisher et al. (2001)</a> expressed a Munc18 mutant with reduced affinity for syntaxin, which specifically modified the kinetics of single-granule exocytotic release events, consistent with an acceleration of fusion pore expansion. This observation demonstrated that Munc18 functions in a late stage in the intracellular membrane fusion process, where its dissociation from syntaxin determines the kinetics of postfusion events. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11157167" 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 study of synaptic vesicle exocytosis in C. elegans unc18 mutants, <a href="#17" class="mim-tip-reference" title="Weimer, R. M., Richmond, J. E., Davis, W. S., Hadwiger, G., Nonet, M. L., Jorgensen, E. M. <strong>Defects in synaptic vesicle docking in unc-18 mutants.</strong> Nature Neurosci. 6: 1023-1030, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12973353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12973353</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12973353[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/nn1118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12973353">Weimer et al. (2003)</a> found a reduction in docked vesicles at the plasma membrane active zone, suggesting that unc18 functions, either directly or indirectly, as a facilitator of vesicle docking. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12973353" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Toonen, R. F. G., Wierda, K., Sons, M. S., de Wit, H., Cornelisse, L. N., Brussaard, A., Plomp, J. J., Verhage, M. <strong>Munc18-1 expression levels control synapse recovery by regulating readily releasable pool size.</strong> Proc. Nat. Acad. Sci. 103: 18332-18337, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17110441/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17110441</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17110441[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.0608507103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17110441">Toonen et al. (2006)</a> found that synapses from Munc18-1 +/- mice displayed increased depression during intense stimulation at glutamatergic, GABAergic, and neuromuscular synapses. This depression was due to a smaller readily releasable pool (RRP) of synaptic vesicles. Conversely, overexpression of Munc18-1 made these synapses recover faster, which was due to a larger RRP and enhanced activity-dependent RRP replenishment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17110441" 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>SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins comprise the core fusion machinery in which cognate vesicle-associated (v-) and target membrane-associated (t-) SNAREs assemble into SNAREpins to bring 2 membranes into close apposition and fuse. Using a reconstituted lipid bilayer system with mammalian SNARE components, <a href="#13" class="mim-tip-reference" title="Shen, J., Tareste, D. C., Paumet, F., Rothman, J. E., Melia, T. J. <strong>Selective activation of cognate SNAREpins by Sec1/Munc18 proteins.</strong> Cell 128: 183-195, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17218264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17218264</a>] [<a href="https://doi.org/10.1016/j.cell.2006.12.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17218264">Shen et al. (2007)</a> showed that rat Munc18-1 accelerated the fusion reaction through direct contact with both t- and v-SNAREs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17218264" 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>During synaptic vesicle fusion, the SNARE protein syntaxin-1 (<a href="/entry/186590">186590</a>) exhibits 2 conformations that both bind to Munc18-1: a 'closed' conformation outside the SNARE complex and an 'open' conformation in the SNARE complex. <a href="#4" class="mim-tip-reference" title="Gerber, S. H., Rah, J.-C., Min, S.-W., Liu, X., de Wit, H., Dulubova, I., Meyer, A. C., Rizo, J., Arancillo, M., Hammer, R. E., Verhage, M., Rosenmund, C., Sudhof, T. C. <strong>Conformational switch of syntaxin-1 controls synaptic vesicle fusion.</strong> Science 321: 1507-1510, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18703708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18703708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18703708[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.1163174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18703708">Gerber et al. (2008)</a> generated knockin/knockout mice that expressed only open syntaxin-1B. Syntaxin-1B(Open) mice were viable but succumbed to generalized seizures at 2 to 3 months of age. Binding of Munc18-1 to syntaxin-1B was impaired in syntaxin-1B(Open) synapses, and the size of the readily releasable vesicle pool was decreased; however, the rate of synaptic vesicle fusion was dramatically enhanced. Thus, <a href="#4" class="mim-tip-reference" title="Gerber, S. H., Rah, J.-C., Min, S.-W., Liu, X., de Wit, H., Dulubova, I., Meyer, A. C., Rizo, J., Arancillo, M., Hammer, R. E., Verhage, M., Rosenmund, C., Sudhof, T. C. <strong>Conformational switch of syntaxin-1 controls synaptic vesicle fusion.</strong> Science 321: 1507-1510, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18703708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18703708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18703708[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.1163174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18703708">Gerber et al. (2008)</a> concluded that the closed conformation of syntaxin-1 gates the initiation of the synaptic vesicle fusion reaction, which is then mediated by SNARE complex/Munc18-1 assemblies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18703708" 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="#18" class="mim-tip-reference" title="Wierda, K. D. B., Toonen, R. F. G., de Wit, H., Brussaard, A. B., Verhage, M. <strong>Interdependence of PKC-dependent and PKC-independent pathways for presynaptic plasticity.</strong> Neuron 54: 275-290, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17442248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17442248</a>] [<a href="https://doi.org/10.1016/j.neuron.2007.04.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17442248">Wierda et al. (2007)</a> stated that MUNC18-1 is essential for presynaptic vesicle release and is rapidly phosphorylated by protein kinase C (PKC: <a href="/entry/176960">176960</a>) upon depolarization. They found that diacylglycerol (DAG)- and phorbol ester-induced potentiation of excitatory postsynaptic currents in mouse neurons depended on both direct activation of Munc13 (UNC13B; <a href="/entry/605836">605836</a>) and PKC-mediated phosphorylation of Munc18-1. <a href="#18" class="mim-tip-reference" title="Wierda, K. D. B., Toonen, R. F. G., de Wit, H., Brussaard, A. B., Verhage, M. <strong>Interdependence of PKC-dependent and PKC-independent pathways for presynaptic plasticity.</strong> Neuron 54: 275-290, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17442248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17442248</a>] [<a href="https://doi.org/10.1016/j.neuron.2007.04.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17442248">Wierda et al. (2007)</a> hypothesized that the 2 pathways may operate separately during different steps in the synaptic vesicle cycle or may converge and cooperate at a single step in the cycle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17442248" 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="Ma, C., Su, L., Seven, A. B., Xu, Y., Rizo, J. <strong>Reconstitution of the vital functions of Munc18 and Munc13 in neurotransmitter release.</strong> Science 339: 421-425, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23258414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23258414</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23258414[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.1230473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23258414">Ma et al. (2013)</a> found that Munc18-1 could displace SNAP25 (<a href="/entry/600322">600322</a>) from syntaxin-1 and that fusion of syntaxin-1-Munc18-1 liposomes with synaptobrevin (see <a href="/entry/185880">185880</a>) liposomes required Munc13, in addition to SNAP25 and synaptotagmin-1 (<a href="/entry/185605">185605</a>)-Ca(2+). Moreover, when starting with syntaxin-1-SNAP25 liposomes, NSF (N-ethylmaleimide-sensitive factor)-alpha-SNAP disassembled the syntaxin-1-SNAP25 heterodimers and abrogated fusion, which then required Munc18-1 and Munc13. <a href="#9" class="mim-tip-reference" title="Ma, C., Su, L., Seven, A. B., Xu, Y., Rizo, J. <strong>Reconstitution of the vital functions of Munc18 and Munc13 in neurotransmitter release.</strong> Science 339: 421-425, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23258414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23258414</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23258414[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.1230473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23258414">Ma et al. (2013)</a> proposed that fusion does not proceed through syntaxin-1-SNAP25 heterodimers but starts with the syntaxin-1-Munc18-1 complex; Munc18-1 and Munc13 then orchestrate membrane fusion together with the SNAREs and synaptotagmin-1-Ca(2+) in an NSF- and SNAP-resistant manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23258414" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 4 unrelated Japanese patients with developmental and epileptic encephalopathy-4 (DEE4; <a href="/entry/612164">612164</a>), <a href="#12" class="mim-tip-reference" title="Saitsu, H., Kato, M., Mizuguchi, T., Hamada, K., Osaka, H., Tohyama, J., Uruno, K., Kumada, S., Nishiyama, K., Nishimura, A., Okada, I., Yoshimura, Y., Hirai, S., Kumada, T., Hayasaka, K., Fukuda, A., Ogata, K., Matsumoto, N. <strong>De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy.</strong> Nature Genet. 40: 782-788, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18469812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18469812</a>] [<a href="https://doi.org/10.1038/ng.150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18469812">Saitsu et al. (2008)</a> identified heterozygous missense mutations in the STXBP1 gene (<a href="#0001">602926.0001</a>-<a href="#0004">602926.0004</a>). The mutations were proven to occur de novo in 3 patients. All mutations occurred in the hydrophobic core of the protein and were predicted to result in destabilization and disruption of protein structure. In vitro studies of the mutant proteins suggested a tendency for aggregation. The phenotype included early-onset seizures, suppression-burst pattern on EEG, and profoundly impaired intellectual development. <a href="#12" class="mim-tip-reference" title="Saitsu, H., Kato, M., Mizuguchi, T., Hamada, K., Osaka, H., Tohyama, J., Uruno, K., Kumada, S., Nishiyama, K., Nishimura, A., Okada, I., Yoshimura, Y., Hirai, S., Kumada, T., Hayasaka, K., Fukuda, A., Ogata, K., Matsumoto, N. <strong>De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy.</strong> Nature Genet. 40: 782-788, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18469812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18469812</a>] [<a href="https://doi.org/10.1038/ng.150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18469812">Saitsu et al. (2008)</a> postulated that the mutations resulted in STXBP1 haploinsufficiency, causing impaired synaptic vesicle release and the DEE phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18469812" 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 2 unrelated French Canadian patients with severe mental retardation and epilepsy, <a href="#6" class="mim-tip-reference" title="Hamdan, F. F., Piton, A., Gauthier, J., Lortie, A., Dubeau, F., Dobrzeniecka, S., Spiegelman, D., Noreau, A., Pellerin, S., Cote, M., Henrion, E., Fombonne, E., Mottron, L., Marineau, C., Drapeau, P., Lafreniere, R. G., Lacaille, J. C., Rouleau, G. A., Michaud, J. L. <strong>De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy.</strong> Ann. Neurol. 65: 748-753, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19557857/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19557857</a>] [<a href="https://doi.org/10.1002/ana.21625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19557857">Hamdan et al. (2009)</a> identified respective de novo heterozygous truncating mutations in the STXBP1 gene (<a href="#0005">602926.0005</a> and <a href="#0006">602926.0006</a>). The patients were ascertained from a larger group of 95 patients with idiopathic mental retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19557857" 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 an 11-year-old boy with DEE4, who had a clinical diagnosis of Dravet syndrome, <a href="#1" class="mim-tip-reference" title="Carvill, G. L., Weckhuysen, S., McMahon, J. M., Hartmann, C., Moller, R. S., Hjalgrim, H., Cook, J., Geraghty, E., O'Roak, B. J., Petrou, S., Clarke, A., Gill, D., and 14 others. <strong>GABRA1 and STXBP1: novel genetic causes of Dravet syndrome.</strong> Neurology 82: 1245-1253, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24623842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24623842</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24623842">Carvill et al. (2014)</a> identified a de novo heterozygous missense mutation in the STXBP1 gene (E283K; <a href="#0008">602926.0008</a>). The mutation was found by whole-exome sequencing. Targeted resequencing of 67 patients with a similar disorder identified 2 additional probands with de novo heterozygous missense mutations in the STXBP1 gene. Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24623842" 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="Kovacevic, J., Maroteaux, G., Schut, D., Loos, M., Dubey, M., Pitsch, J., Remmelink, E., Koopmans, B., Crowley, J., Cornelisse, L. N., Sullivan, P. F., Schoch, S., Toonen, R. F., Stiedl, O., Verhage, M. <strong>Protein instability, haploinsufficiency, and cortical hyper-excitability underlie STXBP1 encephalopathy.</strong> Brain 141: 1350-1374, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29538625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29538625</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29538625[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/brain/awy046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29538625">Kovacevic et al. (2018)</a> found that expression of human STXBP1 with DEE4-causing mutations in Stxbp1 +/- mouse neurons produced normal phenotypes, whereas expression of the same mutants in Stxbp1 -/- mouse neurons produced diverse phenotypes consistent with haploinsufficiency. Further analysis showed that the STXBP1 mutants exhibited severely reduced cellular stability, especially when expressed in HEK293 cells, but also when expressed in primary mouse neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29538625" 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 2 sibs with DEE4, <a href="#8" class="mim-tip-reference" title="Lammertse, H. C. A., van Berkel, A. A., Iacomino, M., Toonen, R. F., Striano, P., Gambardella, A., Verhage, M., Zara, F. <strong>Homozygous STXBP1 variant causes encephalopathy and gain-of-function in synaptic transmission.</strong> Brain 143: 441-451, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31855252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31855252</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31855252[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/brain/awz391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31855252">Lammertse et al. (2020)</a> identified a homozygous missense mutation in the STXBP1 gene (L446F; <a href="#0009">602926.0009</a>). The patients' mother and asymptomatic sib were heterozygous for the mutation; the father was not available for study. Expression of STXBP1 with the L446F mutation in STXBP1-null mouse neurons resulted in shorter dendrites and fewer synapses per dendrite compared to cells expressing wildtype STXBP1. Patch-clamp studies in the mutant cells demonstrated an increased evoked synaptic transmission and impaired recovery after high-frequency stimulation. This appeared to be due to an increased synaptic vesicle response after stimulation with a single action potential. <a href="#8" class="mim-tip-reference" title="Lammertse, H. C. A., van Berkel, A. A., Iacomino, M., Toonen, R. F., Striano, P., Gambardella, A., Verhage, M., Zara, F. <strong>Homozygous STXBP1 variant causes encephalopathy and gain-of-function in synaptic transmission.</strong> Brain 143: 441-451, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31855252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31855252</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31855252[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/brain/awz391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31855252">Lammertse et al. (2020)</a> concluded that the L446F mutation leads to a gain-of-function pathogenic mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31855252" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a review of clinical and molecular data from 271 patients with DEE4, <a href="#19" class="mim-tip-reference" title="Xian, J., Parthasarathy, S., Ruggiero, S. M., Balagura, G., Fitch, E., Helbig, K., Gan, J., Ganesan, S., Kaufman, M. C., Ellis, C. A., Lewis-Smith, D., Galer, P., and 42 others. <strong>Assessing the landscape of STXBP1-related disorders in 534 individuals.</strong> Brain 145: 1668-1683, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35190816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35190816</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35190816[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/brain/awab327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35190816">Xian et al. (2022)</a> identified 54 recurrent mutations in the STXBP1 gene. Sixteen of the mutations were identified in 5 or more patients, with the most common mutations being R406H (in 20 patients), R406C (in 20 patients), and R292H (in 18 patients). Compared to the entire cohort of patients, those with recurrent mutations did not show an overall phenotypic similarity. However, patients with R406H and R406C mutations were more likely to have a burst suppression pattern on EEG and spastic tetraplegia, and less likely to have ataxia, compared to the rest of the cohort. Additionally, patients with premature termination mutations or deletions in the STXBP1 gene were more likely to have infantile spasms, hypsarrhythmia on EEG, ataxia, hypotonia, and neonatal seizure onset compared to patients with missense mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35190816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#16" class="mim-tip-reference" title="Verhage, M., Maia, A. S., Plomp, J. J., Brussaard, A. B., Heeroma, J. H., Vermeer, H., Toonen, R. F., Hammer, R. E., van den Berg, T. K., Missler, M., Geuze, H. J., Sudhof, T. C. <strong>Synaptic assembly of the brain in the absence of neurotransmitter secretion.</strong> Science 287: 864-869, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10657302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10657302</a>] [<a href="https://doi.org/10.1126/science.287.5454.864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10657302">Verhage et al. (2000)</a> abolished Munc18-1 in mice by homologous recombination. This resulted in a completely paralyzed organism. Null mutant embryos were alive until birth but died immediately after birth, probably because they could not breathe. Despite the general, complete, and permanent loss of synaptic transmission in knockout mice, their brains were assembled correctly. Neuronal proliferation, migration, and differentiation into specific brain areas were unaffected. By embryonic day 12, brains from null mutant and control littermates were morphologically indistinguishable. At birth, late-forming brain areas such as the neocortex appeared identical in null mutant and control littermates. After initial brain assembly, extensive cell death of mature neurons was observed in null mutants, occurring first in lower brain areas that mature and form synapses relatively early. The degeneration in the mutant brains exhibited all characteristics of apoptosis. Ablation of Munc18-1 renders the brain synaptically silent, identifying Munc18-1 as the currently most upstream essential protein in neurotransmitter release. <a href="#16" class="mim-tip-reference" title="Verhage, M., Maia, A. S., Plomp, J. J., Brussaard, A. B., Heeroma, J. H., Vermeer, H., Toonen, R. F., Hammer, R. E., van den Berg, T. K., Missler, M., Geuze, H. J., Sudhof, T. C. <strong>Synaptic assembly of the brain in the absence of neurotransmitter secretion.</strong> Science 287: 864-869, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10657302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10657302</a>] [<a href="https://doi.org/10.1126/science.287.5454.864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10657302">Verhage et al. (2000)</a> concluded that synaptic connectivity does not depend on neurotransmitter secretion, but its maintenance does. Neurotransmitter secretion probably functions to validate already established synaptic connections. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10657302" 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="Kovacevic, J., Maroteaux, G., Schut, D., Loos, M., Dubey, M., Pitsch, J., Remmelink, E., Koopmans, B., Crowley, J., Cornelisse, L. N., Sullivan, P. F., Schoch, S., Toonen, R. F., Stiedl, O., Verhage, M. <strong>Protein instability, haploinsufficiency, and cortical hyper-excitability underlie STXBP1 encephalopathy.</strong> Brain 141: 1350-1374, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29538625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29538625</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29538625[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/brain/awy046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29538625">Kovacevic et al. (2018)</a> found that Stxbp1 +/- mice of different genomic backgrounds recapitulated the human DEE4 phenotype, with epileptic spasms, often during inactivity, accompanied by slow-wave discharges that could be suppressed partially by the antiepileptic drug levetiracetam. Stxbp1 +/- mice also showed impaired behavioral flexibility, increased anxiety, and hyperactivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29538625" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>9 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=602926[MIM]" class="btn btn-default mim-tip-hint" role="button" 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>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918317 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918317;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=rs121918317" 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=rs121918317" 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=RCV000007118 OR RCV003588557" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007118, RCV003588557" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007118...</a>
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<p>In a Japanese man (patient 3) with developmental and epileptic encephalopathy-4 (DEE4; <a href="/entry/612164">612164</a>), <a href="#12" class="mim-tip-reference" title="Saitsu, H., Kato, M., Mizuguchi, T., Hamada, K., Osaka, H., Tohyama, J., Uruno, K., Kumada, S., Nishiyama, K., Nishimura, A., Okada, I., Yoshimura, Y., Hirai, S., Kumada, T., Hayasaka, K., Fukuda, A., Ogata, K., Matsumoto, N. <strong>De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy.</strong> Nature Genet. 40: 782-788, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18469812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18469812</a>] [<a href="https://doi.org/10.1038/ng.150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18469812">Saitsu et al. (2008)</a> identified a heterozygous c.1631G-A transition in the STXBP1 gene, resulting in a gly544-to-asp (G544D) substitution. The patient developed seizures by age 10 days with a suppression-burst pattern on EEG, although the seizures remitted by 3 months of age. At age 37 years, he had profoundly impaired intellectual development and spastic paraplegia. The mutation was not found in 500 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18469812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 4</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918318 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918318;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=rs121918318" 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=rs121918318" 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=RCV000007119 OR RCV002311507" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007119, RCV002311507" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007119...</a>
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<p>In a Japanese boy (patient 6) with developmental and epileptic encephalopathy-4 (DEE4; <a href="/entry/612164">612164</a>), <a href="#12" class="mim-tip-reference" title="Saitsu, H., Kato, M., Mizuguchi, T., Hamada, K., Osaka, H., Tohyama, J., Uruno, K., Kumada, S., Nishiyama, K., Nishimura, A., Okada, I., Yoshimura, Y., Hirai, S., Kumada, T., Hayasaka, K., Fukuda, A., Ogata, K., Matsumoto, N. <strong>De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy.</strong> Nature Genet. 40: 782-788, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18469812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18469812</a>] [<a href="https://doi.org/10.1038/ng.150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18469812">Saitsu et al. (2008)</a> identified a de novo heterozygous c.539G-A transition in the STXBP1 gene, resulting in a cys180-to-tyr (C180Y) substitution. He had infantile onset of tonic and myoclonic seizures with suppression-burst pattern and hypsarrhythmia, delayed brain myelination, and spastic quadriplegia. In vitro studies showed that the mutant protein had impaired structural stability, lower thermostability, and decreased binding to several functional synaptic proteins. <a href="#12" class="mim-tip-reference" title="Saitsu, H., Kato, M., Mizuguchi, T., Hamada, K., Osaka, H., Tohyama, J., Uruno, K., Kumada, S., Nishiyama, K., Nishimura, A., Okada, I., Yoshimura, Y., Hirai, S., Kumada, T., Hayasaka, K., Fukuda, A., Ogata, K., Matsumoto, N. <strong>De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy.</strong> Nature Genet. 40: 782-788, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18469812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18469812</a>] [<a href="https://doi.org/10.1038/ng.150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18469812">Saitsu et al. (2008)</a> concluded that this patient had impaired release of synaptic vesicles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18469812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 4</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918319 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918319;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=rs121918319" 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=rs121918319" 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=RCV000007120" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007120" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007120</a>
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<p>In a Japanese girl (patient 7) with developmental and epileptic encephalopathy-4 (DEE4; <a href="/entry/612164">612164</a>), <a href="#12" class="mim-tip-reference" title="Saitsu, H., Kato, M., Mizuguchi, T., Hamada, K., Osaka, H., Tohyama, J., Uruno, K., Kumada, S., Nishiyama, K., Nishimura, A., Okada, I., Yoshimura, Y., Hirai, S., Kumada, T., Hayasaka, K., Fukuda, A., Ogata, K., Matsumoto, N. <strong>De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy.</strong> Nature Genet. 40: 782-788, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18469812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18469812</a>] [<a href="https://doi.org/10.1038/ng.150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18469812">Saitsu et al. (2008)</a> identified a de novo heterozygous c.1328T-G transversion in the STXBP1 gene, resulting in a met443-to-arg (M443R) substitution. She developed intractable seizures at 2 months of age, and later showed profoundly impaired psychomotor development. Brain MRI showed delayed myelination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18469812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 4</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918320 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918320;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=rs121918320" 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=rs121918320" 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=RCV000007121" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007121" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007121</a>
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<p>In a Japanese boy (patient 11) with developmental and epileptic encephalopathy-4 (DEE4; <a href="/entry/612164">612164</a>), <a href="#12" class="mim-tip-reference" title="Saitsu, H., Kato, M., Mizuguchi, T., Hamada, K., Osaka, H., Tohyama, J., Uruno, K., Kumada, S., Nishiyama, K., Nishimura, A., Okada, I., Yoshimura, Y., Hirai, S., Kumada, T., Hayasaka, K., Fukuda, A., Ogata, K., Matsumoto, N. <strong>De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy.</strong> Nature Genet. 40: 782-788, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18469812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18469812</a>] [<a href="https://doi.org/10.1038/ng.150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18469812">Saitsu et al. (2008)</a> identified a de novo heterozygous c.251T-A transversion in the STXBP1 gene, resulting in a val84-to-asp (V84D) substitution. The patient developed tonic seizures at age 2 months with suppression-burst pattern and hypsarrhythmia, and later showed profound mental retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18469812" 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">rs121918321 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918321;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=rs121918321" 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=rs121918321" 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=RCV000007122 OR RCV000189612 OR RCV000539734 OR RCV001265424 OR RCV001266381" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007122, RCV000189612, RCV000539734, RCV001265424, RCV001266381" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007122...</a>
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<p>In a 15-year-old French Canadian boy with developmental and epileptic encephalopathy (DEE4; <a href="/entry/612164">612164</a>), <a href="#6" class="mim-tip-reference" title="Hamdan, F. F., Piton, A., Gauthier, J., Lortie, A., Dubeau, F., Dobrzeniecka, S., Spiegelman, D., Noreau, A., Pellerin, S., Cote, M., Henrion, E., Fombonne, E., Mottron, L., Marineau, C., Drapeau, P., Lafreniere, R. G., Lacaille, J. C., Rouleau, G. A., Michaud, J. L. <strong>De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy.</strong> Ann. Neurol. 65: 748-753, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19557857/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19557857</a>] [<a href="https://doi.org/10.1002/ana.21625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19557857">Hamdan et al. (2009)</a> identified a de novo heterozygous c.1162C-T transition in exon 14 of the STXBP1 gene, resulting in an arg388-to-ter (R388X) substitution, predicted to truncate the domain-3 region, which together with domain-1 provides a binding surface for syntaxin-1 (<a href="/entry/186590">186590</a>). The patient had severe mental retardation, with hypotonia, abnormal gait, tremor, and seizures. Onset of seizures occurred at age 2 years, 9 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19557857" 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">rs587776641 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776641;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=rs587776641" 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=rs587776641" 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=RCV000007123" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007123" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007123</a>
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<p>In a 27-year-old French Canadian man with developmental and epileptic encephalopathy (DEE4; <a href="/entry/612164">612164</a>), <a href="#6" class="mim-tip-reference" title="Hamdan, F. F., Piton, A., Gauthier, J., Lortie, A., Dubeau, F., Dobrzeniecka, S., Spiegelman, D., Noreau, A., Pellerin, S., Cote, M., Henrion, E., Fombonne, E., Mottron, L., Marineau, C., Drapeau, P., Lafreniere, R. G., Lacaille, J. C., Rouleau, G. A., Michaud, J. L. <strong>De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy.</strong> Ann. Neurol. 65: 748-753, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19557857/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19557857</a>] [<a href="https://doi.org/10.1002/ana.21625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19557857">Hamdan et al. (2009)</a> identified a de novo heterozygous G-to-A transition in intron 3 of the STXBP1 gene, resulting in the creation of a stop codon downstream of exon 3. The mutation truncated the domain-1 region, which is implicated in binding to syntaxin-1. The patient had severe mental retardation, with hypotonia, abnormal gait, tremor, and seizures. Onset of seizures occurred at age 6 weeks. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19557857" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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STXBP1, 1-BP DEL, 1206T
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2131510073 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2131510073;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=rs2131510073" 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=rs2131510073" 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=RCV000032659" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032659" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032659</a>
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<p>This variant is classified as a variant of unknown significance because its contribution to nonsyndromic mental retardation has not been confirmed.</p><p>By targeted sequencing of the STXBP1 gene in 50 patients with nonsyndromic mental retardation, <a href="#5" class="mim-tip-reference" title="Hamdan, F. F., Gauthier, J., Dobrzeniecka, S., Lortie, A., Mottron, L., Vanasse, M., D'Anjou, G., Lacaille, J. C., Rouleau, G. A., Michaud, J. L. <strong>Intellectual disability without epilepsy associated with STXBP1 disruption.</strong> Europ. J. Hum. Genet. 19: 607-609, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21364700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21364700</a>] [<a href="https://doi.org/10.1038/ejhg.2010.183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21364700">Hamdan et al. (2011)</a> identified 1 patient of French Canadian origin with a de novo heterozygous 1-bp deletion (1206delT) in domain 3 of the gene, resulting in a frameshift and premature termination (Y402X). The variation was not found in 190 French Canadian controls. The patient was a 21-year-old man who showed global developmental delay and severe mental retardation with limited speech. He had no history of seizures, but did have diffuse tremor of the extremities and an abnormal gait. EEG showed intermittent slow dysfunction in the temporal area; brain CT was normal. <a href="#5" class="mim-tip-reference" title="Hamdan, F. F., Gauthier, J., Dobrzeniecka, S., Lortie, A., Mottron, L., Vanasse, M., D'Anjou, G., Lacaille, J. C., Rouleau, G. A., Michaud, J. L. <strong>Intellectual disability without epilepsy associated with STXBP1 disruption.</strong> Europ. J. Hum. Genet. 19: 607-609, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21364700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21364700</a>] [<a href="https://doi.org/10.1038/ejhg.2010.183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21364700">Hamdan et al. (2011)</a> suggested that this variant may be pathogenic because truncation of the C. elegans ortholog downstream of Y402 results in defects in synaptic vesicle docking (<a href="#17" class="mim-tip-reference" title="Weimer, R. M., Richmond, J. E., Davis, W. S., Hadwiger, G., Nonet, M. L., Jorgensen, E. M. <strong>Defects in synaptic vesicle docking in unc-18 mutants.</strong> Nature Neurosci. 6: 1023-1030, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12973353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12973353</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12973353[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/nn1118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12973353">Weimer et al., 2003</a>) and Stxbp1 haploinsufficiency causes impaired neurotransmission in mice (<a href="#15" class="mim-tip-reference" title="Toonen, R. F. G., Wierda, K., Sons, M. S., de Wit, H., Cornelisse, L. N., Brussaard, A., Plomp, J. J., Verhage, M. <strong>Munc18-1 expression levels control synapse recovery by regulating readily releasable pool size.</strong> Proc. Nat. Acad. Sci. 103: 18332-18337, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17110441/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17110441</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17110441[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.0608507103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17110441">Toonen et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12973353+21364700+17110441" 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">rs587777310 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777310;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=rs587777310" 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=rs587777310" 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=RCV000114939 OR RCV000440506 OR RCV000525775" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000114939, RCV000440506, RCV000525775" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000114939...</a>
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<p>In an 11-year-old boy (T1915) with developmental and epileptic encephalopathy (DEE4; <a href="/entry/612164">612164</a>), who was clinically diagnosed with Dravet syndrome, <a href="#1" class="mim-tip-reference" title="Carvill, G. L., Weckhuysen, S., McMahon, J. M., Hartmann, C., Moller, R. S., Hjalgrim, H., Cook, J., Geraghty, E., O'Roak, B. J., Petrou, S., Clarke, A., Gill, D., and 14 others. <strong>GABRA1 and STXBP1: novel genetic causes of Dravet syndrome.</strong> Neurology 82: 1245-1253, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24623842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24623842</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24623842">Carvill et al. (2014)</a> identified a de novo heterozygous c.847G-A transition in the STXBP1 gene, resulting in a glu283-to-lys (E283K) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the Exome Sequencing Project database. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24623842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 4</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002444403" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002444403" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002444403</a>
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<p>In 2 sibs with autosomal recessive developmental and epileptic encephalopathy (DEE4; <a href="/entry/612164">612164</a>), <a href="#8" class="mim-tip-reference" title="Lammertse, H. C. A., van Berkel, A. A., Iacomino, M., Toonen, R. F., Striano, P., Gambardella, A., Verhage, M., Zara, F. <strong>Homozygous STXBP1 variant causes encephalopathy and gain-of-function in synaptic transmission.</strong> Brain 143: 441-451, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31855252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31855252</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31855252[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/brain/awz391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31855252">Lammertse et al. (2020)</a> identified homozygosity for a c.1336C-T transition in exon 15 of the STXBP1 gene, resulting in a leu446-to-phe (L446F) substitution at a conserved residue. The mutation was identified by whole-exome sequencing. The patients' mother and an asymptomatic sib were mutation carriers; the father was not available for study. Expression of STXBP1 with the L446F mutation in STXBP1-null mouse neurons resulted in shorter dendrites and fewer synapses per dendrite compared to cells expressing wildtype STXBP1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31855252" 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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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9545644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9545644</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9545644" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1997.5202" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Toonen2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Toonen, R. F. G., Wierda, K., Sons, M. S., de Wit, H., Cornelisse, L. N., Brussaard, A., Plomp, J. J., Verhage, M.
|
|
<strong>Munc18-1 expression levels control synapse recovery by regulating readily releasable pool size.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 18332-18337, 2006.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17110441/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17110441</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17110441[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=17110441" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0608507103" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Verhage2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Verhage, M., Maia, A. S., Plomp, J. J., Brussaard, A. B., Heeroma, J. H., Vermeer, H., Toonen, R. F., Hammer, R. E., van den Berg, T. K., Missler, M., Geuze, H. J., Sudhof, T. C.
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|
<strong>Synaptic assembly of the brain in the absence of neurotransmitter secretion.</strong>
|
|
Science 287: 864-869, 2000.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10657302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10657302</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10657302" 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.287.5454.864" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Weimer2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weimer, R. M., Richmond, J. E., Davis, W. S., Hadwiger, G., Nonet, M. L., Jorgensen, E. M.
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<strong>Defects in synaptic vesicle docking in unc-18 mutants.</strong>
|
|
Nature Neurosci. 6: 1023-1030, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12973353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12973353</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12973353[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=12973353" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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[<a href="https://doi.org/10.1038/nn1118" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Wierda2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wierda, K. D. B., Toonen, R. F. G., de Wit, H., Brussaard, A. B., Verhage, M.
|
|
<strong>Interdependence of PKC-dependent and PKC-independent pathways for presynaptic plasticity.</strong>
|
|
Neuron 54: 275-290, 2007.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17442248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17442248</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17442248" 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.neuron.2007.04.001" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Xian2022" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xian, J., Parthasarathy, S., Ruggiero, S. M., Balagura, G., Fitch, E., Helbig, K., Gan, J., Ganesan, S., Kaufman, M. C., Ellis, C. A., Lewis-Smith, D., Galer, P., and 42 others.
|
|
<strong>Assessing the landscape of STXBP1-related disorders in 534 individuals.</strong>
|
|
Brain 145: 1668-1683, 2022.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35190816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35190816</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35190816[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=35190816" 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/brain/awab327" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="20" class="mim-anchor"></a>
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<a id="Yang2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yang, R., Puranam, R. S., Butler, L. S., Qian, W.-H., He, X.-P., Moyer, M. B., Blackburn, K., Andrews, P. I., McNamara, J. O.
|
|
<strong>Autoimmunity to Munc-18 in Rasmussen's encephalitis.</strong>
|
|
Neuron 28: 375-383, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11144349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11144349</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11144349" 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/s0896-6273(00)00118-5" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 11/22/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 03/20/2020<br>Cassandra L. Kniffin - updated : 4/21/2014<br>Ada Hamosh - updated : 2/21/2013<br>Cassandra L. Kniffin - updated : 1/2/2013<br>Patricia A. Hartz - updated : 2/11/2011<br>Cassandra L. Kniffin - updated : 11/5/2009<br>Ada Hamosh - updated : 9/29/2008<br>Cassandra L. Kniffin - updated : 7/10/2008<br>Patricia A. Hartz - updated : 1/4/2008<br>Patricia A. Hartz - updated : 2/8/2007<br>Cassandra L. Kniffin - updated : 8/26/2005<br>Cassandra L. Kniffin - updated : 9/12/2003<br>Ada Hamosh - updated : 2/5/2001<br>Ada Hamosh - updated : 2/2/2000
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Rebekah S. Rasooly : 8/4/1998
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 11/23/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 11/22/2022<br>carol : 11/22/2022<br>carol : 10/13/2020<br>ckniffin : 10/13/2020<br>carol : 10/09/2020<br>carol : 10/05/2020<br>mgross : 03/20/2020<br>carol : 04/22/2014<br>mcolton : 4/22/2014<br>ckniffin : 4/21/2014<br>carol : 9/26/2013<br>alopez : 2/25/2013<br>terry : 2/21/2013<br>carol : 1/10/2013<br>ckniffin : 1/2/2013<br>mgross : 2/16/2011<br>terry : 2/11/2011<br>wwang : 11/18/2009<br>ckniffin : 11/5/2009<br>alopez : 9/30/2008<br>terry : 9/29/2008<br>alopez : 7/18/2008<br>alopez : 7/18/2008<br>ckniffin : 7/10/2008<br>mgross : 1/16/2008<br>terry : 1/4/2008<br>alopez : 2/8/2007<br>wwang : 9/6/2005<br>ckniffin : 8/26/2005<br>alopez : 10/16/2003<br>carol : 9/16/2003<br>ckniffin : 9/12/2003<br>alopez : 2/7/2001<br>alopez : 2/7/2001<br>terry : 2/5/2001<br>alopez : 2/3/2000<br>terry : 2/2/2000<br>mgross : 3/8/1999<br>psherman : 1/21/1999<br>alopez : 8/4/1998
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
|
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<strong>*</strong> 602926
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</span>
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</h3>
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</div>
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<div>
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<h3>
|
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<span class="mim-font">
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|
|
SYNTAXIN-BINDING PROTEIN 1; STXBP1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
|
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
UNC18, C. ELEGANS, HOMOLOG OF, 1<br />
|
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MUNC18-1
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: STXBP1</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 768666006;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong>
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<em>
|
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Cytogenetic location: 9q34.11
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Genomic coordinates <span class="small">(GRCh38)</span> : 9:127,611,912-127,696,029 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<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>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
|
|
|
<tr>
|
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<td rowspan="1">
|
|
<span class="mim-font">
|
|
9q34.11
|
|
</span>
|
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</td>
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Developmental and epileptic encephalopathy 4
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
612164
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Autosomal recessive
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>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>Within the secretory pathway, proteins and other cargo are transferred from one compartment to another by vesicular traffic. Transport vesicles bud from donor membranes and dock to specific acceptor compartments. The S. cerevisiae protein Sec1 participates in the constitutive secretory pathway between the Golgi apparatus and the plasma membrane. Pevsner et al. (1994) identified rat Stxbp1, which they called n-Sec1. The predicted 68-kD n-Sec1 protein shares 27% identity with S. cerevisiae Sec1 and 59% identity with C. elegans Unc18. RNA blot analysis showed that n-Sec1 mRNA expression was neural-specific. </p><p>Since Unc18 mutation leads to severe paralysis and presynaptic acetylcholine accumulation, Unc18 has been implicated in neurotransmitter release. Gengyo-Ando et al. (1996) identified cDNAs encoding 2 mouse Unc18 homologs, a neural-specific protein called Munc18-1 and a ubiquitous protein called Munc18-3. They used the murine cDNAs to isolate human Munc18-1 cDNAs from a fetal brain cDNA library. The sequences of the predicted 594-amino acid mouse and human Munc18-1 proteins are identical. Gengyo-Ando et al. (1996) found that Munc18-1 complemented the locomotion and cholinergic defects in Unc18 mutant animals. </p><p>By Northern blot analysis of human tissues, Swanson et al. (1998) determined that STXBP1 is expressed as a 4-kb transcript in various tissues. The highest levels of expression were observed in retina and cerebellum. RT-PCR analysis revealed an additional, alternatively spliced form of STXBP1 in retina and cerebellum. This mRNA contains an additional exon and encodes a predicted 603-amino acid protein. Two alternatively spliced forms of STXBP1 are also found in rat, and the predicted proteins are identical to their human counterparts. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hamdan et al. (2009) stated that the STXBP1 gene contains 20 exons and that alternative splicing results in 2 isoforms with and without exon 19. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By fluorescence in situ hybridization, Swanson et al. (1998) mapped the STXBP1 gene to chromosome 9q34.1. </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>Pevsner et al. (1994) found that rat n-Sec1 is a neural-specific, syntaxin (see 186590)-binding protein that may participate in the regulation of synaptic vesicle docking and fusion. </p><p>Yang et al. (2000) identified high titer autoantibodies against Munc18 in the serum and CSF of a single patient with Rasmussen encephalitis, a rare disorder characterized by progressive degeneration of a single cerebral hemisphere and intractable seizures. The patient had previously been reported by Rogers et al. (1994) who identified autoantibodies against GLUR3 (GRIA3; 305915) in serum and CSF. Weak immunoreactivity to Munc18 was found in 3 of 14 additional patients with Rasmussen encephalitis, but often only on prolonged exposure or multiple experiments. As Munc18 is a cytosolic protein, Yang et al. (2000) hypothesized that humoral attack on GluR3 would first damage neurons, thus exposing Munc18 and leading to expanded immune attack. Both proteins are involved in synaptic transmission; immune attack on these proteins may have acted synergistically to produce a severe neurologic phenotype. </p><p>In adrenal chromaffin cells, Fisher et al. (2001) expressed a Munc18 mutant with reduced affinity for syntaxin, which specifically modified the kinetics of single-granule exocytotic release events, consistent with an acceleration of fusion pore expansion. This observation demonstrated that Munc18 functions in a late stage in the intracellular membrane fusion process, where its dissociation from syntaxin determines the kinetics of postfusion events. </p><p>In a study of synaptic vesicle exocytosis in C. elegans unc18 mutants, Weimer et al. (2003) found a reduction in docked vesicles at the plasma membrane active zone, suggesting that unc18 functions, either directly or indirectly, as a facilitator of vesicle docking. </p><p>Toonen et al. (2006) found that synapses from Munc18-1 +/- mice displayed increased depression during intense stimulation at glutamatergic, GABAergic, and neuromuscular synapses. This depression was due to a smaller readily releasable pool (RRP) of synaptic vesicles. Conversely, overexpression of Munc18-1 made these synapses recover faster, which was due to a larger RRP and enhanced activity-dependent RRP replenishment. </p><p>SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins comprise the core fusion machinery in which cognate vesicle-associated (v-) and target membrane-associated (t-) SNAREs assemble into SNAREpins to bring 2 membranes into close apposition and fuse. Using a reconstituted lipid bilayer system with mammalian SNARE components, Shen et al. (2007) showed that rat Munc18-1 accelerated the fusion reaction through direct contact with both t- and v-SNAREs. </p><p>During synaptic vesicle fusion, the SNARE protein syntaxin-1 (186590) exhibits 2 conformations that both bind to Munc18-1: a 'closed' conformation outside the SNARE complex and an 'open' conformation in the SNARE complex. Gerber et al. (2008) generated knockin/knockout mice that expressed only open syntaxin-1B. Syntaxin-1B(Open) mice were viable but succumbed to generalized seizures at 2 to 3 months of age. Binding of Munc18-1 to syntaxin-1B was impaired in syntaxin-1B(Open) synapses, and the size of the readily releasable vesicle pool was decreased; however, the rate of synaptic vesicle fusion was dramatically enhanced. Thus, Gerber et al. (2008) concluded that the closed conformation of syntaxin-1 gates the initiation of the synaptic vesicle fusion reaction, which is then mediated by SNARE complex/Munc18-1 assemblies. </p><p>Wierda et al. (2007) stated that MUNC18-1 is essential for presynaptic vesicle release and is rapidly phosphorylated by protein kinase C (PKC: 176960) upon depolarization. They found that diacylglycerol (DAG)- and phorbol ester-induced potentiation of excitatory postsynaptic currents in mouse neurons depended on both direct activation of Munc13 (UNC13B; 605836) and PKC-mediated phosphorylation of Munc18-1. Wierda et al. (2007) hypothesized that the 2 pathways may operate separately during different steps in the synaptic vesicle cycle or may converge and cooperate at a single step in the cycle. </p><p>Ma et al. (2013) found that Munc18-1 could displace SNAP25 (600322) from syntaxin-1 and that fusion of syntaxin-1-Munc18-1 liposomes with synaptobrevin (see 185880) liposomes required Munc13, in addition to SNAP25 and synaptotagmin-1 (185605)-Ca(2+). Moreover, when starting with syntaxin-1-SNAP25 liposomes, NSF (N-ethylmaleimide-sensitive factor)-alpha-SNAP disassembled the syntaxin-1-SNAP25 heterodimers and abrogated fusion, which then required Munc18-1 and Munc13. Ma et al. (2013) proposed that fusion does not proceed through syntaxin-1-SNAP25 heterodimers but starts with the syntaxin-1-Munc18-1 complex; Munc18-1 and Munc13 then orchestrate membrane fusion together with the SNAREs and synaptotagmin-1-Ca(2+) in an NSF- and SNAP-resistant manner. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 4 unrelated Japanese patients with developmental and epileptic encephalopathy-4 (DEE4; 612164), Saitsu et al. (2008) identified heterozygous missense mutations in the STXBP1 gene (602926.0001-602926.0004). The mutations were proven to occur de novo in 3 patients. All mutations occurred in the hydrophobic core of the protein and were predicted to result in destabilization and disruption of protein structure. In vitro studies of the mutant proteins suggested a tendency for aggregation. The phenotype included early-onset seizures, suppression-burst pattern on EEG, and profoundly impaired intellectual development. Saitsu et al. (2008) postulated that the mutations resulted in STXBP1 haploinsufficiency, causing impaired synaptic vesicle release and the DEE phenotype. </p><p>In 2 unrelated French Canadian patients with severe mental retardation and epilepsy, Hamdan et al. (2009) identified respective de novo heterozygous truncating mutations in the STXBP1 gene (602926.0005 and 602926.0006). The patients were ascertained from a larger group of 95 patients with idiopathic mental retardation. </p><p>In an 11-year-old boy with DEE4, who had a clinical diagnosis of Dravet syndrome, Carvill et al. (2014) identified a de novo heterozygous missense mutation in the STXBP1 gene (E283K; 602926.0008). The mutation was found by whole-exome sequencing. Targeted resequencing of 67 patients with a similar disorder identified 2 additional probands with de novo heterozygous missense mutations in the STXBP1 gene. Functional studies of the variants were not performed. </p><p>Kovacevic et al. (2018) found that expression of human STXBP1 with DEE4-causing mutations in Stxbp1 +/- mouse neurons produced normal phenotypes, whereas expression of the same mutants in Stxbp1 -/- mouse neurons produced diverse phenotypes consistent with haploinsufficiency. Further analysis showed that the STXBP1 mutants exhibited severely reduced cellular stability, especially when expressed in HEK293 cells, but also when expressed in primary mouse neurons. </p><p>In 2 sibs with DEE4, Lammertse et al. (2020) identified a homozygous missense mutation in the STXBP1 gene (L446F; 602926.0009). The patients' mother and asymptomatic sib were heterozygous for the mutation; the father was not available for study. Expression of STXBP1 with the L446F mutation in STXBP1-null mouse neurons resulted in shorter dendrites and fewer synapses per dendrite compared to cells expressing wildtype STXBP1. Patch-clamp studies in the mutant cells demonstrated an increased evoked synaptic transmission and impaired recovery after high-frequency stimulation. This appeared to be due to an increased synaptic vesicle response after stimulation with a single action potential. Lammertse et al. (2020) concluded that the L446F mutation leads to a gain-of-function pathogenic mechanism. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In a review of clinical and molecular data from 271 patients with DEE4, Xian et al. (2022) identified 54 recurrent mutations in the STXBP1 gene. Sixteen of the mutations were identified in 5 or more patients, with the most common mutations being R406H (in 20 patients), R406C (in 20 patients), and R292H (in 18 patients). Compared to the entire cohort of patients, those with recurrent mutations did not show an overall phenotypic similarity. However, patients with R406H and R406C mutations were more likely to have a burst suppression pattern on EEG and spastic tetraplegia, and less likely to have ataxia, compared to the rest of the cohort. Additionally, patients with premature termination mutations or deletions in the STXBP1 gene were more likely to have infantile spasms, hypsarrhythmia on EEG, ataxia, hypotonia, and neonatal seizure onset compared to patients with missense mutations. </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>Verhage et al. (2000) abolished Munc18-1 in mice by homologous recombination. This resulted in a completely paralyzed organism. Null mutant embryos were alive until birth but died immediately after birth, probably because they could not breathe. Despite the general, complete, and permanent loss of synaptic transmission in knockout mice, their brains were assembled correctly. Neuronal proliferation, migration, and differentiation into specific brain areas were unaffected. By embryonic day 12, brains from null mutant and control littermates were morphologically indistinguishable. At birth, late-forming brain areas such as the neocortex appeared identical in null mutant and control littermates. After initial brain assembly, extensive cell death of mature neurons was observed in null mutants, occurring first in lower brain areas that mature and form synapses relatively early. The degeneration in the mutant brains exhibited all characteristics of apoptosis. Ablation of Munc18-1 renders the brain synaptically silent, identifying Munc18-1 as the currently most upstream essential protein in neurotransmitter release. Verhage et al. (2000) concluded that synaptic connectivity does not depend on neurotransmitter secretion, but its maintenance does. Neurotransmitter secretion probably functions to validate already established synaptic connections. </p><p>Kovacevic et al. (2018) found that Stxbp1 +/- mice of different genomic backgrounds recapitulated the human DEE4 phenotype, with epileptic spasms, often during inactivity, accompanied by slow-wave discharges that could be suppressed partially by the antiepileptic drug levetiracetam. Stxbp1 +/- mice also showed impaired behavioral flexibility, increased anxiety, and hyperactivity. </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">
|
|
<strong>ALLELIC VARIANTS</strong>
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</span>
|
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<strong>9 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">
|
|
<strong>.0001 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 4</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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STXBP1, GLY544ASP
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<br />
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SNP: rs121918317,
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ClinVar: RCV000007118, RCV003588557
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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 Japanese man (patient 3) with developmental and epileptic encephalopathy-4 (DEE4; 612164), Saitsu et al. (2008) identified a heterozygous c.1631G-A transition in the STXBP1 gene, resulting in a gly544-to-asp (G544D) substitution. The patient developed seizures by age 10 days with a suppression-burst pattern on EEG, although the seizures remitted by 3 months of age. At age 37 years, he had profoundly impaired intellectual development and spastic paraplegia. The mutation was not found in 500 control chromosomes. </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>.0002 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 4</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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STXBP1, CYS180TYR
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<br />
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SNP: rs121918318,
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ClinVar: RCV000007119, RCV002311507
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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 Japanese boy (patient 6) with developmental and epileptic encephalopathy-4 (DEE4; 612164), Saitsu et al. (2008) identified a de novo heterozygous c.539G-A transition in the STXBP1 gene, resulting in a cys180-to-tyr (C180Y) substitution. He had infantile onset of tonic and myoclonic seizures with suppression-burst pattern and hypsarrhythmia, delayed brain myelination, and spastic quadriplegia. In vitro studies showed that the mutant protein had impaired structural stability, lower thermostability, and decreased binding to several functional synaptic proteins. Saitsu et al. (2008) concluded that this patient had impaired release of synaptic vesicles. </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>.0003 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 4</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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STXBP1, MET443ARG
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<br />
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SNP: rs121918319,
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ClinVar: RCV000007120
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a Japanese girl (patient 7) with developmental and epileptic encephalopathy-4 (DEE4; 612164), Saitsu et al. (2008) identified a de novo heterozygous c.1328T-G transversion in the STXBP1 gene, resulting in a met443-to-arg (M443R) substitution. She developed intractable seizures at 2 months of age, and later showed profoundly impaired psychomotor development. Brain MRI showed delayed myelination. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0004 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 4</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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STXBP1, VAL84ASP
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<br />
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SNP: rs121918320,
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ClinVar: RCV000007121
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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 Japanese boy (patient 11) with developmental and epileptic encephalopathy-4 (DEE4; 612164), Saitsu et al. (2008) identified a de novo heterozygous c.251T-A transversion in the STXBP1 gene, resulting in a val84-to-asp (V84D) substitution. The patient developed tonic seizures at age 2 months with suppression-burst pattern and hypsarrhythmia, and later showed profound mental retardation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0005 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 4</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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STXBP1, ARG388TER
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<br />
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SNP: rs121918321,
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ClinVar: RCV000007122, RCV000189612, RCV000539734, RCV001265424, RCV001266381
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 15-year-old French Canadian boy with developmental and epileptic encephalopathy (DEE4; 612164), Hamdan et al. (2009) identified a de novo heterozygous c.1162C-T transition in exon 14 of the STXBP1 gene, resulting in an arg388-to-ter (R388X) substitution, predicted to truncate the domain-3 region, which together with domain-1 provides a binding surface for syntaxin-1 (186590). The patient had severe mental retardation, with hypotonia, abnormal gait, tremor, and seizures. Onset of seizures occurred at age 2 years, 9 months. </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>.0006 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 4</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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STXBP1, IVS3DS, G-A, +1
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<br />
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SNP: rs587776641,
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ClinVar: RCV000007123
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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 27-year-old French Canadian man with developmental and epileptic encephalopathy (DEE4; 612164), Hamdan et al. (2009) identified a de novo heterozygous G-to-A transition in intron 3 of the STXBP1 gene, resulting in the creation of a stop codon downstream of exon 3. The mutation truncated the domain-1 region, which is implicated in binding to syntaxin-1. The patient had severe mental retardation, with hypotonia, abnormal gait, tremor, and seizures. Onset of seizures occurred at age 6 weeks. </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>.0007 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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STXBP1, 1-BP DEL, 1206T
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<br />
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SNP: rs2131510073,
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ClinVar: RCV000032659
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<p>This variant is classified as a variant of unknown significance because its contribution to nonsyndromic mental retardation has not been confirmed.</p><p>By targeted sequencing of the STXBP1 gene in 50 patients with nonsyndromic mental retardation, Hamdan et al. (2011) identified 1 patient of French Canadian origin with a de novo heterozygous 1-bp deletion (1206delT) in domain 3 of the gene, resulting in a frameshift and premature termination (Y402X). The variation was not found in 190 French Canadian controls. The patient was a 21-year-old man who showed global developmental delay and severe mental retardation with limited speech. He had no history of seizures, but did have diffuse tremor of the extremities and an abnormal gait. EEG showed intermittent slow dysfunction in the temporal area; brain CT was normal. Hamdan et al. (2011) suggested that this variant may be pathogenic because truncation of the C. elegans ortholog downstream of Y402 results in defects in synaptic vesicle docking (Weimer et al., 2003) and Stxbp1 haploinsufficiency causes impaired neurotransmission in mice (Toonen et al., 2006). </p>
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<h4>
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<span class="mim-font">
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<strong>.0008 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 4</strong>
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</span>
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</h4>
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STXBP1, GLU283LYS
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<br />
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SNP: rs587777310,
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ClinVar: RCV000114939, RCV000440506, RCV000525775
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<p>In an 11-year-old boy (T1915) with developmental and epileptic encephalopathy (DEE4; 612164), who was clinically diagnosed with Dravet syndrome, Carvill et al. (2014) identified a de novo heterozygous c.847G-A transition in the STXBP1 gene, resulting in a glu283-to-lys (E283K) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the Exome Sequencing Project database. Functional studies of the variant were not performed. </p>
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<h4>
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<span class="mim-font">
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<strong>.0009 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 4</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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STXBP1, LEU446PHE
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<br />
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ClinVar: RCV002444403
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<p>In 2 sibs with autosomal recessive developmental and epileptic encephalopathy (DEE4; 612164), Lammertse et al. (2020) identified homozygosity for a c.1336C-T transition in exon 15 of the STXBP1 gene, resulting in a leu446-to-phe (L446F) substitution at a conserved residue. The mutation was identified by whole-exome sequencing. The patients' mother and an asymptomatic sib were mutation carriers; the father was not available for study. Expression of STXBP1 with the L446F mutation in STXBP1-null mouse neurons resulted in shorter dendrites and fewer synapses per dendrite compared to cells expressing wildtype STXBP1. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<strong>GABRA1 and STXBP1: novel genetic causes of Dravet syndrome.</strong>
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Gerber, S. H., Rah, J.-C., Min, S.-W., Liu, X., de Wit, H., Dulubova, I., Meyer, A. C., Rizo, J., Arancillo, M., Hammer, R. E., Verhage, M., Rosenmund, C., Sudhof, T. C.
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<strong>Intellectual disability without epilepsy associated with STXBP1 disruption.</strong>
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Hamdan, F. F., Piton, A., Gauthier, J., Lortie, A., Dubeau, F., Dobrzeniecka, S., Spiegelman, D., Noreau, A., Pellerin, S., Cote, M., Henrion, E., Fombonne, E., Mottron, L., Marineau, C., Drapeau, P., Lafreniere, R. G., Lacaille, J. C., Rouleau, G. A., Michaud, J. L.
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<strong>De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy.</strong>
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Kovacevic, J., Maroteaux, G., Schut, D., Loos, M., Dubey, M., Pitsch, J., Remmelink, E., Koopmans, B., Crowley, J., Cornelisse, L. N., Sullivan, P. F., Schoch, S., Toonen, R. F., Stiedl, O., Verhage, M.
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<strong>Protein instability, haploinsufficiency, and cortical hyper-excitability underlie STXBP1 encephalopathy.</strong>
|
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Brain 141: 1350-1374, 2018.
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[PubMed: 29538625]
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[Full Text: https://doi.org/10.1093/brain/awy046]
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<p class="mim-text-font">
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Lammertse, H. C. A., van Berkel, A. A., Iacomino, M., Toonen, R. F., Striano, P., Gambardella, A., Verhage, M., Zara, F.
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<strong>Homozygous STXBP1 variant causes encephalopathy and gain-of-function in synaptic transmission.</strong>
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Ma, C., Su, L., Seven, A. B., Xu, Y., Rizo, J.
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<p class="mim-text-font">
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Pevsner, J., Hsu, S.-C., Scheller, R. H.
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<strong>n-Sec1: a neural-specific syntaxin-binding protein.</strong>
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<p class="mim-text-font">
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Rogers, S. W., Andrews, P. I., Gahring, L. C., Whisenand, T., Cauley, K., Crain, B., Hughes, T. E., Heinemann, S. F., McNamara, J. O.
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<strong>Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis.</strong>
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Science 265: 648-651, 1994.
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[PubMed: 8036512]
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[Full Text: https://doi.org/10.1126/science.8036512]
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Saitsu, H., Kato, M., Mizuguchi, T., Hamada, K., Osaka, H., Tohyama, J., Uruno, K., Kumada, S., Nishiyama, K., Nishimura, A., Okada, I., Yoshimura, Y., Hirai, S., Kumada, T., Hayasaka, K., Fukuda, A., Ogata, K., Matsumoto, N.
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<strong>De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy.</strong>
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Shen, J., Tareste, D. C., Paumet, F., Rothman, J. E., Melia, T. J.
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<strong>Selective activation of cognate SNAREpins by Sec1/Munc18 proteins.</strong>
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Swanson, D. A., Steel, J. M., Valle, D.
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Toonen, R. F. G., Wierda, K., Sons, M. S., de Wit, H., Cornelisse, L. N., Brussaard, A., Plomp, J. J., Verhage, M.
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Verhage, M., Maia, A. S., Plomp, J. J., Brussaard, A. B., Heeroma, J. H., Vermeer, H., Toonen, R. F., Hammer, R. E., van den Berg, T. K., Missler, M., Geuze, H. J., Sudhof, T. C.
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<p class="mim-text-font">
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Weimer, R. M., Richmond, J. E., Davis, W. S., Hadwiger, G., Nonet, M. L., Jorgensen, E. M.
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<p class="mim-text-font">
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Wierda, K. D. B., Toonen, R. F. G., de Wit, H., Brussaard, A. B., Verhage, M.
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<li>
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<p class="mim-text-font">
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Xian, J., Parthasarathy, S., Ruggiero, S. M., Balagura, G., Fitch, E., Helbig, K., Gan, J., Ganesan, S., Kaufman, M. C., Ellis, C. A., Lewis-Smith, D., Galer, P., and 42 others.
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<strong>Assessing the landscape of STXBP1-related disorders in 534 individuals.</strong>
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Brain 145: 1668-1683, 2022.
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[PubMed: 35190816]
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[Full Text: https://doi.org/10.1093/brain/awab327]
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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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Yang, R., Puranam, R. S., Butler, L. S., Qian, W.-H., He, X.-P., Moyer, M. B., Blackburn, K., Andrews, P. I., McNamara, J. O.
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<strong>Autoimmunity to Munc-18 in Rasmussen's encephalitis.</strong>
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Neuron 28: 375-383, 2000.
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[PubMed: 11144349]
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[Full Text: https://doi.org/10.1016/s0896-6273(00)00118-5]
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</p>
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</li>
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</ol>
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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 class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 11/22/2022<br>Bao Lige - updated : 03/20/2020<br>Cassandra L. Kniffin - updated : 4/21/2014<br>Ada Hamosh - updated : 2/21/2013<br>Cassandra L. Kniffin - updated : 1/2/2013<br>Patricia A. Hartz - updated : 2/11/2011<br>Cassandra L. Kniffin - updated : 11/5/2009<br>Ada Hamosh - updated : 9/29/2008<br>Cassandra L. Kniffin - updated : 7/10/2008<br>Patricia A. Hartz - updated : 1/4/2008<br>Patricia A. Hartz - updated : 2/8/2007<br>Cassandra L. Kniffin - updated : 8/26/2005<br>Cassandra L. Kniffin - updated : 9/12/2003<br>Ada Hamosh - updated : 2/5/2001<br>Ada Hamosh - updated : 2/2/2000
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</span>
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Rebekah S. Rasooly : 8/4/1998
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Edit History:
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carol : 11/23/2022<br>carol : 11/22/2022<br>carol : 11/22/2022<br>carol : 10/13/2020<br>ckniffin : 10/13/2020<br>carol : 10/09/2020<br>carol : 10/05/2020<br>mgross : 03/20/2020<br>carol : 04/22/2014<br>mcolton : 4/22/2014<br>ckniffin : 4/21/2014<br>carol : 9/26/2013<br>alopez : 2/25/2013<br>terry : 2/21/2013<br>carol : 1/10/2013<br>ckniffin : 1/2/2013<br>mgross : 2/16/2011<br>terry : 2/11/2011<br>wwang : 11/18/2009<br>ckniffin : 11/5/2009<br>alopez : 9/30/2008<br>terry : 9/29/2008<br>alopez : 7/18/2008<br>alopez : 7/18/2008<br>ckniffin : 7/10/2008<br>mgross : 1/16/2008<br>terry : 1/4/2008<br>alopez : 2/8/2007<br>wwang : 9/6/2005<br>ckniffin : 8/26/2005<br>alopez : 10/16/2003<br>carol : 9/16/2003<br>ckniffin : 9/12/2003<br>alopez : 2/7/2001<br>alopez : 2/7/2001<br>terry : 2/5/2001<br>alopez : 2/3/2000<br>terry : 2/2/2000<br>mgross : 3/8/1999<br>psherman : 1/21/1999<br>alopez : 8/4/1998
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