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<title>
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Entry
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- *605032 - COMPLEXIN 1; CPLX1
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- OMIM
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</ul>
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</nav>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="row">
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<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
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<div class="form-group">
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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</li>
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<li role="separator" class="divider"></li>
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<li>
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<a href="/history"> Search History </a>
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</li>
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</ul>
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</div>
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</div>
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<div class="autocomplete" id="mimEntrySearchAutocomplete"></div>
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</div>
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</div>
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<div class="col-lg-4 col-md-4 col-sm-4 col-xs-4">
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<span class="small">
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</form>
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<div class="row">
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<p />
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</div>
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<!-- <div id="mimSearch"> -->
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<div class="container hidden-print">
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
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<div id="mimAlertBanner">
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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-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*605032</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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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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</li>
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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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
|
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<a href="/allelicVariants/605032">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
|
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
|
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<a href="#editHistory"><strong>Edit History</strong></a>
|
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</li>
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</ul>
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</nav>
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</div>
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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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|
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000168993;t=ENST00000304062" 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=10815" 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=605032" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
|
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
|
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</span>
|
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</span>
|
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</div>
|
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000168993;t=ENST00000304062" 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_006651,XM_011513391" 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_006651" 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=605032" 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">
|
|
<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
|
</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=09233&isoform_id=09233_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/CPLX1" 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/2465459,5729781,5921800,12803307,30582897,119603053,119603054,119603055,189065139,326205313,608785237,767928946,2462594630" 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/O14810" 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=10815" 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=ENSG00000168993;t=ENST00000304062" 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=CPLX1" 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=CPLX1" 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+10815" 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/CPLX1" 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:10815" 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/10815" 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=chr4&hgg_gene=ENST00000304062.11&hgg_start=784957&hgg_end=826129&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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=605032[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=605032[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000168993" 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=CPLX1" 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=CPLX1" 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=CPLX1" 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=CPLX1&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/PA26826" 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:2309" 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/FBgn0041605.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:104727" 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/CPLX1#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:104727" 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/10815/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=10815" 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=WBGene00022271;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-161221-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
|
<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">
|
|
<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:10815" 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=CPLX1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
605032
|
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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>
|
|
<span class="mim-font">
|
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|
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COMPLEXIN 1; CPLX1
|
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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>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
CPX1<br />
|
|
SYNAPHIN 2
|
|
</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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CPLX1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CPLX1</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/4/17?start=-3&limit=10&highlight=17">4p16.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr4:784957-826129&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'})">4:784,957-826,129</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
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|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/4/17?start=-3&limit=10&highlight=17">
|
|
4p16.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Developmental and epileptic encephalopathy 63
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/617976"> 617976 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
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<p>The highly specialized uptake and exocytosis system of synaptic vesicle traffic has been studied extensively as a model of membrane fusion. The fusion reaction begins with the assembly of a core complex consisting of the plasma membrane proteins syntaxin (e.g., STX1A; <a href="/entry/186590">186590</a>) and SNAP25 (<a href="/entry/600322">600322</a>) and the synaptic vesicle protein synaptobrevin (e.g., VAMP2; <a href="/entry/185881">185881</a>). The core complex then serves as a soluble NSF attachment protein (SNAP; see <a href="/entry/603215">603215</a>) receptor, or SNARE. Binding of SNAP to SNARE leads to ATP-dependent binding of NSF (<a href="/entry/601633">601633</a>), which subsequently catalyzes disruption of the SNARE complex. Synaptotagmin (e.g., SYT1; <a href="/entry/185605">185605</a>) triggers the final step in the fusion process, possibly via Ca(2+)-dependent interaction with syntaxin. Complexins, such as CPLX1, are soluble proteins that regulate SNARE function during membrane fusion (<a href="#7" class="mim-tip-reference" title="McMahon, H. T., Missler, M., Li, C., Sudhof, T. C. <strong>Complexins: cytosolic proteins that regulate SNAP receptor function.</strong> Cell 83: 111-119, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7553862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7553862</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90239-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7553862">McMahon et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7553862" 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 immunoprecipitating the SNARE core complex from rat brain homogenates using syntaxin antibodies, followed by SDS-PAGE analysis, <a href="#7" class="mim-tip-reference" title="McMahon, H. T., Missler, M., Li, C., Sudhof, T. C. <strong>Complexins: cytosolic proteins that regulate SNAP receptor function.</strong> Cell 83: 111-119, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7553862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7553862</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90239-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7553862">McMahon et al. (1995)</a> identified 18- and 19-kD proteins distinct from synaptobrevin and other members of the complex. The authors designated the 18- and 19-kD proteins complexin-1 (CPLX1) and -2 (CPLX2; <a href="/entry/605033">605033</a>), respectively. By screening rat brain, human temporal cortex, and human hippocampus cDNA libraries with degenerate oligonucleotides corresponding to complexin peptide sequences, <a href="#7" class="mim-tip-reference" title="McMahon, H. T., Missler, M., Li, C., Sudhof, T. C. <strong>Complexins: cytosolic proteins that regulate SNAP receptor function.</strong> Cell 83: 111-119, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7553862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7553862</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90239-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7553862">McMahon et al. (1995)</a> isolated cDNAs encoding rat and human CPLX1 and CPLX2. Sequence analysis determined that the rat Cplx1 and Cplx2 genes encode 134-amino acid, highly charged proteins that share 84% amino acid identity. Asp, glu, lys, and arg account for 44 to 47% of the complexin protein residues. The amino acid sequences, but not the nucleotide sequences, of mouse, rat, and human CPLX2 are 100% identical. Northern blot and Western blot analyses detected abundant expression of Cplx1 and Cplx2 in rat brain; low levels of Cplx1 were also detected in testis, and Cplx2 was detected at low levels in all tissues tested. Immunofluorescence microscopy demonstrated that complexins are largely colocalized with syntaxin and SNAP25, particularly at synapses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7553862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Maximov, A., Tang, J., Yang, X., Pang, Z. P., Sudhof, T. C. <strong>Complexin controls the force transfer from SNARE complexes to membranes in fusion.</strong> Science 323: 516-521, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19164751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19164751</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19164751[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.1166505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19164751">Maximov et al. (2009)</a> stated that the 134-amino acid CPX1 protein has an N-terminal domain, followed by an accessory alpha helix (residues 27 to 46), a central alpha helix (residues 47 to 70) that binds the SNARE complex, and a C-terminal domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19164751" 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>Functional analysis by <a href="#7" class="mim-tip-reference" title="McMahon, H. T., Missler, M., Li, C., Sudhof, T. C. <strong>Complexins: cytosolic proteins that regulate SNAP receptor function.</strong> Cell 83: 111-119, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7553862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7553862</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90239-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7553862">McMahon et al. (1995)</a> showed that complexin binding to syntaxin increased substantially in the presence of SNAP25 and synaptobrevin, and that it was calcium independent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7553862" 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>Complexins, also called synaphins, are cytosolic proteins that preferentially bind to syntaxin within the SNARE complex. Studying squid and rat synaphin, <a href="#11" class="mim-tip-reference" title="Tokumaru, H., Umayahara, K., Pellegrini, L. L., Ishizuka, T., Saisu, H., Betz, H., Augustine, G. J., Abe, T. <strong>SNARE complex oligomerization by synaphin/complexin is essential for synaptic vesicle exocytosis.</strong> Cell 104: 421-432, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239399</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00229-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239399">Tokumaru et al. (2001)</a> found that synaphin promotes SNAREs to form precomplexes that oligomerize into higher-order structures. A peptide from the central, syntaxin-binding domain of synaphin competitively inhibited these 2 proteins from interacting and prevented SNARE complexes from oligomerizing. Injection of this peptide into squid giant presynaptic terminals inhibited neurotransmitter release at a late prefusion step of synaptic vesicle exocytosis. <a href="#11" class="mim-tip-reference" title="Tokumaru, H., Umayahara, K., Pellegrini, L. L., Ishizuka, T., Saisu, H., Betz, H., Augustine, G. J., Abe, T. <strong>SNARE complex oligomerization by synaphin/complexin is essential for synaptic vesicle exocytosis.</strong> Cell 104: 421-432, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239399</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00229-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239399">Tokumaru et al. (2001)</a> proposed that oligomerization of SNARE complexes into a higher-order structure creates a SNARE scaffold for efficient, regulated fusion of synaptic vesicles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239399" 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="Reim, K., Mansour, M., Varoqueaux, F., McMahon, H. T., Sudhof, T. C., Brose, N., Rosenmund, C. <strong>Complexins regulate a late step in Ca(2+)-dependent neurotransmitter release.</strong> Cell 104: 71-81, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11163241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11163241</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00192-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11163241">Reim et al. (2001)</a> demonstrated that complexins are important regulators of transmitter release at a step immediately preceding vesicle fusion. Neurons from mice lacking complexins showed a dramatically reduced transmitter release efficiency due to decreased calcium sensitivity of the synaptic secretion process. Analyses of mutant mouse neurons demonstrated that complexins acted at or following the calcium-triggering step of fast synchronous transmitter release by regulating the exocytotic calcium sensor, its interaction with the core complex fusion machinery, or the efficiency of the fusion apparatus itself. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11163241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Giraudo, C. G., Eng, W. S., Melia, T. J., Rothman, J. E. <strong>A clamping mechanism involved in SNARE-dependent exocytosis.</strong> Science 313: 676-680, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16794037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16794037</a>] [<a href="https://doi.org/10.1126/science.1129450" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16794037">Giraudo et al. (2006)</a> described what may represent a basic principle of the coupling mechanism between synaptic vesicle fusion and calcium: a reversible clamping protein, complexin, that can freeze the SNAREpin, an assembled fusion-competent intermediate, en route to fusion. When calcium binds to the calcium sensor synaptotagmin, the clamp would be released. SNARE proteins, and key regulators like synaptotagmin and complexin, can be ectopically expressed on the cell surface. Cells expressing such 'flipped' synaptic SNAREs fuse constitutively, but when complexin was coexpressed, fusion was blocked. Adding back calcium triggered fusion from this intermediate in the presence of synaptotagmin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16794037" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using biochemical approaches, <a href="#10" class="mim-tip-reference" title="Tang, J., Maximov, A., Shin, O.-H., Dai, H., Rizo, J., Sudhof, T. C. <strong>A complexin/synaptotagmin 1 switch controls fast synaptic vesicle exocytosis.</strong> Cell 126: 1175-1187, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16990140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16990140</a>] [<a href="https://doi.org/10.1016/j.cell.2006.08.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16990140">Tang et al. (2006)</a> showed that SYT1 competed with CPLX1 for SNARE complex binding in a Ca(2+)-dependent manner. Excess CPLX1 blocked fast Ca(2+)-triggered release and exocytosis, but not slow asynchronous release. <a href="#10" class="mim-tip-reference" title="Tang, J., Maximov, A., Shin, O.-H., Dai, H., Rizo, J., Sudhof, T. C. <strong>A complexin/synaptotagmin 1 switch controls fast synaptic vesicle exocytosis.</strong> Cell 126: 1175-1187, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16990140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16990140</a>] [<a href="https://doi.org/10.1016/j.cell.2006.08.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16990140">Tang et al. (2006)</a> proposed that primed metastable vesicles form the substrate for SYT1, which triggers fast synchronous release upon Ca(2+) influx by binding to SNARE complexes, displacing CPLX1, and coupling the SNARE complex to phospholipids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16990140" 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>Fusion between vesicle (v) and target (t) membrane SNAREs is favored energetically and would occur spontaneously in the absence of inhibitory clamping factors, such as CPX1. <a href="#3" class="mim-tip-reference" title="Giraudo, C. G., Garcia-Diaz, A., Eng, W. S., Chen, Y., Hendrickson, W. A., Melia, T. J., Rothman, J. E. <strong>Alternative zippering as an on-off switch for SNARE-mediated fusion.</strong> Science 323: 512-516, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19164750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19164750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19164750[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.1166500" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19164750">Giraudo et al. (2009)</a> noted that in the fused SNARE complex, the central helix of human CPX1 lies along the interface between v- and t-SNAREs, making numerous contacts with both. In contrast, the accessory helix of CPX1 lacks contacts with the SNARE proteins in the fused complex. Using a reconstituted fusion system, <a href="#3" class="mim-tip-reference" title="Giraudo, C. G., Garcia-Diaz, A., Eng, W. S., Chen, Y., Hendrickson, W. A., Melia, T. J., Rothman, J. E. <strong>Alternative zippering as an on-off switch for SNARE-mediated fusion.</strong> Science 323: 512-516, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19164750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19164750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19164750[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.1166500" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19164750">Giraudo et al. (2009)</a> obtained evidence suggesting that the accessory helix of CPX1 functions as an on-off switch for SNARE complex fusion. In their model, the accessory helix assembles with the 3-helix t-SNARE as an alternative to the v-SNARE VAMP2, preventing SNARE zippering and membrane fusion. Activators, like synaptotagmin, would cause the accessory helix to switch out, permitting membrane fusion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19164750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Maximov, A., Tang, J., Yang, X., Pang, Z. P., Sudhof, T. C. <strong>Complexin controls the force transfer from SNARE complexes to membranes in fusion.</strong> Science 323: 516-521, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19164751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19164751</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19164751[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.1166505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19164751">Maximov et al. (2009)</a> showed that complexin both suppressed spontaneous fusion and activated fast Ca(2+)-evoked fusion in mouse neuronal synapses. Deletion analysis showed that the N-terminal 27 amino acids of complexin were required for fast Ca(2+)-activated fusion, and that the accessory helix was required for clamping of spontaneous fusion. <a href="#6" class="mim-tip-reference" title="Maximov, A., Tang, J., Yang, X., Pang, Z. P., Sudhof, T. C. <strong>Complexin controls the force transfer from SNARE complexes to membranes in fusion.</strong> Science 323: 516-521, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19164751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19164751</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19164751[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.1166505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19164751">Maximov et al. (2009)</a> noted that the N-terminal complexin sequence lies near the point where SNARE complexes insert into the 2 fusing membranes. They proposed that complexin stabilizes SNARE complexes in a 'superprimed' position, and that synaptotagmin subsequently triggers complexin release, as well as initiating Ca(2+)-dependent phospholipid binding, membrane fusion, and neurotransmitter release. <a href="#6" class="mim-tip-reference" title="Maximov, A., Tang, J., Yang, X., Pang, Z. P., Sudhof, T. C. <strong>Complexin controls the force transfer from SNARE complexes to membranes in fusion.</strong> Science 323: 516-521, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19164751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19164751</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19164751[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.1166505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19164751">Maximov et al. (2009)</a> concluded that synaptotagmin and complexin operate as interdependent clamp-activators of SNARE-dependent fusion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19164751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 sisters with developmental and epileptic encephalopathy-63 (DEE63; <a href="/entry/617976">617976</a>), <a href="#5" class="mim-tip-reference" title="Karaca, E., Harel, T., Pehlivan, D., Jhangiani, S. N., Gambin, T., Akdemir, Z. C., Gonzaga-Jauregui, C., Erdin, S., Bayram, Y., Campbell, I. M., Hunter, J. V., Atik, M. M., and 52 others. <strong>Genes that affect brain structure and function identified by rare variant analyses of mendelian neurologic disease.</strong> Neuron 88: 499-513, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26539891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26539891</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26539891[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2015.09.048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26539891">Karaca et al. (2015)</a> identified a homozygous nonsense mutation in the CPLX1 gene (E108X; <a href="#0001">605032.0001</a>), consistent with a complete loss of function. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but <a href="#5" class="mim-tip-reference" title="Karaca, E., Harel, T., Pehlivan, D., Jhangiani, S. N., Gambin, T., Akdemir, Z. C., Gonzaga-Jauregui, C., Erdin, S., Bayram, Y., Campbell, I. M., Hunter, J. V., Atik, M. M., and 52 others. <strong>Genes that affect brain structure and function identified by rare variant analyses of mendelian neurologic disease.</strong> Neuron 88: 499-513, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26539891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26539891</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26539891[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2015.09.048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26539891">Karaca et al. (2015)</a> noted that the CPLX1 gene is involved in modulating presynaptic neurotransmitter release. The family was part of a cohort of 128 mostly consanguineous families with neurogenetic disorders, often including brain malformations, that underwent whole-exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26539891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 patients from 2 unrelated consanguineous families with DEE63, <a href="#8" class="mim-tip-reference" title="Redler, S., Strom, T. M., Wieland, T., Cremer, K., Engels, H., Distelmaier, F., Schaper, J., Kuchler, A., Lemke, J. R., Jeschke, S., Schreyer, N., Sticht, H., Koch, M., Ludecke, H.-J., Wieczorek, D. <strong>Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.</strong> Europ. J. Hum. Genet. 25: 889-893, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28422131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28422131</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28422131[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/ejhg.2017.52" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28422131">Redler et al. (2017)</a> identified homozygous mutations in the CPLX1 gene. One was a nonsense mutation (C105X; <a href="#0002">605032.0002</a>) and 1 was a missense mutation (L128M; <a href="/entry/605302#0003">605302.0003</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed, but the authors noted that homozygous Cplx1-null mice develop a neurologic disorder manifest as ataxia. The patients were part of a cohort of 311 patients with intellectual disability who underwent whole-exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28422131" 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="#9" class="mim-tip-reference" title="Reim, K., Mansour, M., Varoqueaux, F., McMahon, H. T., Sudhof, T. C., Brose, N., Rosenmund, C. <strong>Complexins regulate a late step in Ca(2+)-dependent neurotransmitter release.</strong> Cell 104: 71-81, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11163241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11163241</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00192-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11163241">Reim et al. (2001)</a> created deletion mutations in the murine Cplx1 and Cplx2 genes and homozygous single and double mutants with their respective controls. They found that mice lacking Cplx2 showed no obvious phenotypic changes. In contrast, homozygous Cplx1 deletion mutants developed a strong ataxia, suffered from sporadic seizures, were unable to reproduce, and died within 2 to 4 months after birth. Although loss of Cplx1 was ultimately fatal, the fact that mice lacking either Cplx1 or Cplx2 lived for at least 2 months after birth indicated that Cplx1 and Cplx2 are partially redundant. They therefore generated double mutants lacking both Cplx isoforms. Homozygous Cplx1/2 double mutants died within a few hours after birth. To detect possible developmental changes or alterations in brain structure due to Cplx deletion mutations, <a href="#9" class="mim-tip-reference" title="Reim, K., Mansour, M., Varoqueaux, F., McMahon, H. T., Sudhof, T. C., Brose, N., Rosenmund, C. <strong>Complexins regulate a late step in Ca(2+)-dependent neurotransmitter release.</strong> Cell 104: 71-81, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11163241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11163241</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00192-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11163241">Reim et al. (2001)</a> analyzed morphologic characteristics of brains from homozygous adult Cplx1 and Cplx2 single mutants as well as newborn Cplx1/2 double mutants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11163241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Glynn, D., Drew, C. J., Reim, K., Brose, N., Morton, A. J. <strong>Profound ataxia in complexin I knockout mice masks a complex phenotype that includes exploratory and habituation deficits.</strong> Hum. Molec. Genet. 14: 2369-2385, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16000319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16000319</a>] [<a href="https://doi.org/10.1093/hmg/ddi239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16000319">Glynn et al. (2005)</a> found that Cplx1 -/- mice showed pronounced deficits in motor coordination and locomotion including abnormal gait, inability to run or swim, impaired rotarod performance, reduced neuromuscular strength, dystonia, and resting tremor. Although the abnormal motor phenotype dominated their overt symptoms, Cplx1 -/- mice also showed behavioral deficits in complex such as grooming, rearing on hindlimbs, and reduced exploration in several different paradigms. They also showed deficits in tasks reflecting emotional reactivity. They failed to habituate to confinement and showed a 'panic' response when exposed to water. Behavioral deficits of Cplx1 -/- mice reflected those predicted from the distribution of complexin I in the brain. <a href="#4" class="mim-tip-reference" title="Glynn, D., Drew, C. J., Reim, K., Brose, N., Morton, A. J. <strong>Profound ataxia in complexin I knockout mice masks a complex phenotype that includes exploratory and habituation deficits.</strong> Hum. Molec. Genet. 14: 2369-2385, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16000319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16000319</a>] [<a href="https://doi.org/10.1093/hmg/ddi239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16000319">Glynn et al. (2005)</a> concluded that complexin I is essential not only for normal motor function in mice, but also for normal performance of other complex behaviors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16000319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Drew, C. J. G., Kyd, R. J., Morton, A. J. <strong>Complexin 1 knockout mice exhibit marked deficits in social behaviours but appear to be cognitively normal.</strong> Hum. Molec. Genet. 16: 2288-2305, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17652102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17652102</a>] [<a href="https://doi.org/10.1093/hmg/ddm181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17652102">Drew et al. (2007)</a> found that juvenile Cplx1-null mice showed no evidence of cognitive impairment. However, Cplx1-null mice failed in the social transmission of food preference task due to abnormal social interactions rather than due to cognitive impairments or increased anxiety. Cplx1-null mice also failed to demonstrate a preference for social novelty, and male Cplx1-null failed to show the aggressive behavior that is typical of wildtype males toward an intruder mouse. The results showed that, in addition to the severe motor and exploratory deficits already described, Cplx1-null mice have pronounced deficits in social behaviors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17652102" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 sisters (patients BAB6167 and BAB6168), born of consanguineous parents (family HOU2319) with developmental and epileptic encephalopathy-63 (DEE63; <a href="/entry/617976">617976</a>), <a href="#5" class="mim-tip-reference" title="Karaca, E., Harel, T., Pehlivan, D., Jhangiani, S. N., Gambin, T., Akdemir, Z. C., Gonzaga-Jauregui, C., Erdin, S., Bayram, Y., Campbell, I. M., Hunter, J. V., Atik, M. M., and 52 others. <strong>Genes that affect brain structure and function identified by rare variant analyses of mendelian neurologic disease.</strong> Neuron 88: 499-513, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26539891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26539891</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26539891[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2015.09.048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26539891">Karaca et al. (2015)</a> identified a homozygous c.322G-T transversion (c.322G-T, NM_006651) in the CPLX1 gene, resulting in a glu108-to-ter (E108X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed, but <a href="#5" class="mim-tip-reference" title="Karaca, E., Harel, T., Pehlivan, D., Jhangiani, S. N., Gambin, T., Akdemir, Z. C., Gonzaga-Jauregui, C., Erdin, S., Bayram, Y., Campbell, I. M., Hunter, J. V., Atik, M. M., and 52 others. <strong>Genes that affect brain structure and function identified by rare variant analyses of mendelian neurologic disease.</strong> Neuron 88: 499-513, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26539891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26539891</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26539891[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2015.09.048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26539891">Karaca et al. (2015)</a> noted that the CPLX1 gene is involved in modulating presynaptic neurotransmitter release. The family was part of a cohort of 128 mostly consanguineous families with neurogenetic disorders, often including brain malformations, that underwent whole-exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26539891" 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">rs1553851860 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553851860;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=rs1553851860" 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=rs1553851860" 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=RCV000627076" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000627076" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000627076</a>
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<p>In 2 sisters, born of consanguineous Lebanese parents, with developmental and epileptic encephalopathy-63 (DEE63; <a href="/entry/617976">617976</a>), <a href="#8" class="mim-tip-reference" title="Redler, S., Strom, T. M., Wieland, T., Cremer, K., Engels, H., Distelmaier, F., Schaper, J., Kuchler, A., Lemke, J. R., Jeschke, S., Schreyer, N., Sticht, H., Koch, M., Ludecke, H.-J., Wieczorek, D. <strong>Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.</strong> Europ. J. Hum. Genet. 25: 889-893, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28422131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28422131</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28422131[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/ejhg.2017.52" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28422131">Redler et al. (2017)</a> identified a homozygous c.315C-A transversion (c.315C-A, NM_006651.2) in exon 4 of the CPLX1 gene, resulting in a cys105-to-ter (C105X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. The patients had onset of intractable infantile spasms and myoclonic epilepsy in the first weeks to months of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28422131" 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 63</strong>
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CPLX1, LEU128MET (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs371709824;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs371709824</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"><span class="text-primary">●</span> rs371709824 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs371709824;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs371709824?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs371709824" 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=rs371709824" 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=RCV000627077 OR RCV001320840" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000627077, RCV001320840" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000627077...</a>
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<p>In a boy (patient 3), born of consanguineous parents originating from the Turkmen population, with developmental and epileptic encephalopathy-63 (DEE63; <a href="/entry/617976">617976</a>), <a href="#8" class="mim-tip-reference" title="Redler, S., Strom, T. M., Wieland, T., Cremer, K., Engels, H., Distelmaier, F., Schaper, J., Kuchler, A., Lemke, J. R., Jeschke, S., Schreyer, N., Sticht, H., Koch, M., Ludecke, H.-J., Wieczorek, D. <strong>Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.</strong> Europ. J. Hum. Genet. 25: 889-893, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28422131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28422131</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28422131[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/ejhg.2017.52" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28422131">Redler et al. (2017)</a> identified a homozygous c.382C-A transversion (c.382C-A, NM_006651.2) in exon 4 of the CPLX1 gene, resulting in a leu128-to-met (L128M) substitution at a highly conserved residue in the C-terminal domain in a region important for synaptic vesicle binding. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was present in heterozygous state in 6 of 33,197 individuals in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. The patient had onset of refractory myoclonic seizures at 2 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28422131" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="Drew2007" class="mim-anchor"></a>
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Drew, C. J. G., Kyd, R. J., Morton, A. J.
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[<a href="https://doi.org/10.1093/hmg/ddm181" target="_blank">Full Text</a>]
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Giraudo, C. G., Eng, W. S., Melia, T. J., Rothman, J. E.
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<strong>A clamping mechanism involved in SNARE-dependent exocytosis.</strong>
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Science 313: 676-680, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16794037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16794037</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16794037" 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.1129450" target="_blank">Full Text</a>]
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Giraudo, C. G., Garcia-Diaz, A., Eng, W. S., Chen, Y., Hendrickson, W. A., Melia, T. J., Rothman, J. E.
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<strong>Alternative zippering as an on-off switch for SNARE-mediated fusion.</strong>
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Science 323: 512-516, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19164750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19164750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19164750[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=19164750" 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.1166500" target="_blank">Full Text</a>]
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Glynn, D., Drew, C. J., Reim, K., Brose, N., Morton, A. J.
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<strong>Profound ataxia in complexin I knockout mice masks a complex phenotype that includes exploratory and habituation deficits.</strong>
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Hum. Molec. Genet. 14: 2369-2385, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16000319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16000319</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16000319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi239" target="_blank">Full Text</a>]
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Karaca, E., Harel, T., Pehlivan, D., Jhangiani, S. N., Gambin, T., Akdemir, Z. C., Gonzaga-Jauregui, C., Erdin, S., Bayram, Y., Campbell, I. M., Hunter, J. V., Atik, M. M., and 52 others.
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<strong>Genes that affect brain structure and function identified by rare variant analyses of mendelian neurologic disease.</strong>
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Neuron 88: 499-513, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26539891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26539891</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26539891[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=26539891" 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.2015.09.048" target="_blank">Full Text</a>]
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Maximov, A., Tang, J., Yang, X., Pang, Z. P., Sudhof, T. C.
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<strong>Complexin controls the force transfer from SNARE complexes to membranes in fusion.</strong>
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[<a href="https://doi.org/10.1126/science.1166505" target="_blank">Full Text</a>]
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<a id="McMahon1995" class="mim-anchor"></a>
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McMahon, H. T., Missler, M., Li, C., Sudhof, T. C.
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<strong>Complexins: cytosolic proteins that regulate SNAP receptor function.</strong>
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Cell 83: 111-119, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7553862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7553862</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7553862" 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/10.1016/0092-8674(95)90239-2" target="_blank">Full Text</a>]
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<a id="Redler2017" class="mim-anchor"></a>
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Redler, S., Strom, T. M., Wieland, T., Cremer, K., Engels, H., Distelmaier, F., Schaper, J., Kuchler, A., Lemke, J. R., Jeschke, S., Schreyer, N., Sticht, H., Koch, M., Ludecke, H.-J., Wieczorek, D.
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<strong>Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.</strong>
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Europ. J. Hum. Genet. 25: 889-893, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28422131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28422131</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28422131[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=28422131" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ejhg.2017.52" target="_blank">Full Text</a>]
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<a id="Reim2001" class="mim-anchor"></a>
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Reim, K., Mansour, M., Varoqueaux, F., McMahon, H. T., Sudhof, T. C., Brose, N., Rosenmund, C.
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<strong>Complexins regulate a late step in Ca(2+)-dependent neurotransmitter release.</strong>
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Cell 104: 71-81, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11163241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11163241</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11163241" 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/s0092-8674(01)00192-1" target="_blank">Full Text</a>]
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<a id="Tang2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tang, J., Maximov, A., Shin, O.-H., Dai, H., Rizo, J., Sudhof, T. C.
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<strong>A complexin/synaptotagmin 1 switch controls fast synaptic vesicle exocytosis.</strong>
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Cell 126: 1175-1187, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16990140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16990140</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16990140" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.cell.2006.08.030" target="_blank">Full Text</a>]
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<a id="Tokumaru2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tokumaru, H., Umayahara, K., Pellegrini, L. L., Ishizuka, T., Saisu, H., Betz, H., Augustine, G. J., Abe, T.
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<strong>SNARE complex oligomerization by synaphin/complexin is essential for synaptic vesicle exocytosis.</strong>
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Cell 104: 421-432, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239399</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239399" 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/s0092-8674(01)00229-x" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 05/14/2018
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 9/2/2009<br>Patricia A. Hartz - updated : 2/4/2009<br>George E. Tiller - updated : 1/12/2009<br>Paul J. Converse - updated : 12/22/2006<br>Ada Hamosh - updated : 9/6/2006<br>Stylianos E. Antonarakis - updated : 3/8/2001<br>Stylianos E. Antonarakis - updated : 2/1/2001
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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Creation Date:
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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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Paul J. Converse : 6/6/2000
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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 : 06/27/2024
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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alopez : 11/17/2020<br>joanna : 11/04/2020<br>carol : 05/16/2018<br>carol : 05/15/2018<br>ckniffin : 05/14/2018<br>wwang : 09/09/2009<br>ckniffin : 9/2/2009<br>mgross : 2/5/2009<br>mgross : 2/5/2009<br>terry : 2/4/2009<br>wwang : 1/12/2009<br>mgross : 1/2/2007<br>terry : 12/22/2006<br>alopez : 9/11/2006<br>alopez : 9/11/2006<br>terry : 9/6/2006<br>mgross : 12/12/2001<br>mgross : 3/8/2001<br>mgross : 2/1/2001<br>mgross : 6/7/2000<br>mgross : 6/6/2000<br>mgross : 6/6/2000
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<span class="mim-font">
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<strong>*</strong> 605032
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COMPLEXIN 1; CPLX1
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<em>Alternative titles; symbols</em>
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CPX1<br />
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SYNAPHIN 2
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: CPLX1</em></strong>
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Cytogenetic location: 4p16.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 4:784,957-826,129 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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4p16.3
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<span class="mim-font">
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Developmental and epileptic encephalopathy 63
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<span class="mim-font">
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617976
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Autosomal recessive
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>The highly specialized uptake and exocytosis system of synaptic vesicle traffic has been studied extensively as a model of membrane fusion. The fusion reaction begins with the assembly of a core complex consisting of the plasma membrane proteins syntaxin (e.g., STX1A; 186590) and SNAP25 (600322) and the synaptic vesicle protein synaptobrevin (e.g., VAMP2; 185881). The core complex then serves as a soluble NSF attachment protein (SNAP; see 603215) receptor, or SNARE. Binding of SNAP to SNARE leads to ATP-dependent binding of NSF (601633), which subsequently catalyzes disruption of the SNARE complex. Synaptotagmin (e.g., SYT1; 185605) triggers the final step in the fusion process, possibly via Ca(2+)-dependent interaction with syntaxin. Complexins, such as CPLX1, are soluble proteins that regulate SNARE function during membrane fusion (McMahon et al., 1995). </p>
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<strong>Cloning and Expression</strong>
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<p>By immunoprecipitating the SNARE core complex from rat brain homogenates using syntaxin antibodies, followed by SDS-PAGE analysis, McMahon et al. (1995) identified 18- and 19-kD proteins distinct from synaptobrevin and other members of the complex. The authors designated the 18- and 19-kD proteins complexin-1 (CPLX1) and -2 (CPLX2; 605033), respectively. By screening rat brain, human temporal cortex, and human hippocampus cDNA libraries with degenerate oligonucleotides corresponding to complexin peptide sequences, McMahon et al. (1995) isolated cDNAs encoding rat and human CPLX1 and CPLX2. Sequence analysis determined that the rat Cplx1 and Cplx2 genes encode 134-amino acid, highly charged proteins that share 84% amino acid identity. Asp, glu, lys, and arg account for 44 to 47% of the complexin protein residues. The amino acid sequences, but not the nucleotide sequences, of mouse, rat, and human CPLX2 are 100% identical. Northern blot and Western blot analyses detected abundant expression of Cplx1 and Cplx2 in rat brain; low levels of Cplx1 were also detected in testis, and Cplx2 was detected at low levels in all tissues tested. Immunofluorescence microscopy demonstrated that complexins are largely colocalized with syntaxin and SNAP25, particularly at synapses. </p><p>Maximov et al. (2009) stated that the 134-amino acid CPX1 protein has an N-terminal domain, followed by an accessory alpha helix (residues 27 to 46), a central alpha helix (residues 47 to 70) that binds the SNARE complex, and a C-terminal domain. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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<span class="mim-text-font">
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<p>Functional analysis by McMahon et al. (1995) showed that complexin binding to syntaxin increased substantially in the presence of SNAP25 and synaptobrevin, and that it was calcium independent. </p><p>Complexins, also called synaphins, are cytosolic proteins that preferentially bind to syntaxin within the SNARE complex. Studying squid and rat synaphin, Tokumaru et al. (2001) found that synaphin promotes SNAREs to form precomplexes that oligomerize into higher-order structures. A peptide from the central, syntaxin-binding domain of synaphin competitively inhibited these 2 proteins from interacting and prevented SNARE complexes from oligomerizing. Injection of this peptide into squid giant presynaptic terminals inhibited neurotransmitter release at a late prefusion step of synaptic vesicle exocytosis. Tokumaru et al. (2001) proposed that oligomerization of SNARE complexes into a higher-order structure creates a SNARE scaffold for efficient, regulated fusion of synaptic vesicles. </p><p>Reim et al. (2001) demonstrated that complexins are important regulators of transmitter release at a step immediately preceding vesicle fusion. Neurons from mice lacking complexins showed a dramatically reduced transmitter release efficiency due to decreased calcium sensitivity of the synaptic secretion process. Analyses of mutant mouse neurons demonstrated that complexins acted at or following the calcium-triggering step of fast synchronous transmitter release by regulating the exocytotic calcium sensor, its interaction with the core complex fusion machinery, or the efficiency of the fusion apparatus itself. </p><p>Giraudo et al. (2006) described what may represent a basic principle of the coupling mechanism between synaptic vesicle fusion and calcium: a reversible clamping protein, complexin, that can freeze the SNAREpin, an assembled fusion-competent intermediate, en route to fusion. When calcium binds to the calcium sensor synaptotagmin, the clamp would be released. SNARE proteins, and key regulators like synaptotagmin and complexin, can be ectopically expressed on the cell surface. Cells expressing such 'flipped' synaptic SNAREs fuse constitutively, but when complexin was coexpressed, fusion was blocked. Adding back calcium triggered fusion from this intermediate in the presence of synaptotagmin. </p><p>Using biochemical approaches, Tang et al. (2006) showed that SYT1 competed with CPLX1 for SNARE complex binding in a Ca(2+)-dependent manner. Excess CPLX1 blocked fast Ca(2+)-triggered release and exocytosis, but not slow asynchronous release. Tang et al. (2006) proposed that primed metastable vesicles form the substrate for SYT1, which triggers fast synchronous release upon Ca(2+) influx by binding to SNARE complexes, displacing CPLX1, and coupling the SNARE complex to phospholipids. </p><p>Fusion between vesicle (v) and target (t) membrane SNAREs is favored energetically and would occur spontaneously in the absence of inhibitory clamping factors, such as CPX1. Giraudo et al. (2009) noted that in the fused SNARE complex, the central helix of human CPX1 lies along the interface between v- and t-SNAREs, making numerous contacts with both. In contrast, the accessory helix of CPX1 lacks contacts with the SNARE proteins in the fused complex. Using a reconstituted fusion system, Giraudo et al. (2009) obtained evidence suggesting that the accessory helix of CPX1 functions as an on-off switch for SNARE complex fusion. In their model, the accessory helix assembles with the 3-helix t-SNARE as an alternative to the v-SNARE VAMP2, preventing SNARE zippering and membrane fusion. Activators, like synaptotagmin, would cause the accessory helix to switch out, permitting membrane fusion. </p><p>Maximov et al. (2009) showed that complexin both suppressed spontaneous fusion and activated fast Ca(2+)-evoked fusion in mouse neuronal synapses. Deletion analysis showed that the N-terminal 27 amino acids of complexin were required for fast Ca(2+)-activated fusion, and that the accessory helix was required for clamping of spontaneous fusion. Maximov et al. (2009) noted that the N-terminal complexin sequence lies near the point where SNARE complexes insert into the 2 fusing membranes. They proposed that complexin stabilizes SNARE complexes in a 'superprimed' position, and that synaptotagmin subsequently triggers complexin release, as well as initiating Ca(2+)-dependent phospholipid binding, membrane fusion, and neurotransmitter release. Maximov et al. (2009) concluded that synaptotagmin and complexin operate as interdependent clamp-activators of SNARE-dependent fusion. </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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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p>In 2 sisters with developmental and epileptic encephalopathy-63 (DEE63; 617976), Karaca et al. (2015) identified a homozygous nonsense mutation in the CPLX1 gene (E108X; 605032.0001), consistent with a complete loss of function. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but Karaca et al. (2015) noted that the CPLX1 gene is involved in modulating presynaptic neurotransmitter release. The family was part of a cohort of 128 mostly consanguineous families with neurogenetic disorders, often including brain malformations, that underwent whole-exome sequencing. </p><p>In 3 patients from 2 unrelated consanguineous families with DEE63, Redler et al. (2017) identified homozygous mutations in the CPLX1 gene. One was a nonsense mutation (C105X; 605032.0002) and 1 was a missense mutation (L128M; 605302.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed, but the authors noted that homozygous Cplx1-null mice develop a neurologic disorder manifest as ataxia. The patients were part of a cohort of 311 patients with intellectual disability who underwent whole-exome sequencing. </p>
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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 class="mim-text-font">
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<p>Reim et al. (2001) created deletion mutations in the murine Cplx1 and Cplx2 genes and homozygous single and double mutants with their respective controls. They found that mice lacking Cplx2 showed no obvious phenotypic changes. In contrast, homozygous Cplx1 deletion mutants developed a strong ataxia, suffered from sporadic seizures, were unable to reproduce, and died within 2 to 4 months after birth. Although loss of Cplx1 was ultimately fatal, the fact that mice lacking either Cplx1 or Cplx2 lived for at least 2 months after birth indicated that Cplx1 and Cplx2 are partially redundant. They therefore generated double mutants lacking both Cplx isoforms. Homozygous Cplx1/2 double mutants died within a few hours after birth. To detect possible developmental changes or alterations in brain structure due to Cplx deletion mutations, Reim et al. (2001) analyzed morphologic characteristics of brains from homozygous adult Cplx1 and Cplx2 single mutants as well as newborn Cplx1/2 double mutants. </p><p>Glynn et al. (2005) found that Cplx1 -/- mice showed pronounced deficits in motor coordination and locomotion including abnormal gait, inability to run or swim, impaired rotarod performance, reduced neuromuscular strength, dystonia, and resting tremor. Although the abnormal motor phenotype dominated their overt symptoms, Cplx1 -/- mice also showed behavioral deficits in complex such as grooming, rearing on hindlimbs, and reduced exploration in several different paradigms. They also showed deficits in tasks reflecting emotional reactivity. They failed to habituate to confinement and showed a 'panic' response when exposed to water. Behavioral deficits of Cplx1 -/- mice reflected those predicted from the distribution of complexin I in the brain. Glynn et al. (2005) concluded that complexin I is essential not only for normal motor function in mice, but also for normal performance of other complex behaviors. </p><p>Drew et al. (2007) found that juvenile Cplx1-null mice showed no evidence of cognitive impairment. However, Cplx1-null mice failed in the social transmission of food preference task due to abnormal social interactions rather than due to cognitive impairments or increased anxiety. Cplx1-null mice also failed to demonstrate a preference for social novelty, and male Cplx1-null failed to show the aggressive behavior that is typical of wildtype males toward an intruder mouse. The results showed that, in addition to the severe motor and exploratory deficits already described, Cplx1-null mice have pronounced deficits in social behaviors. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>3 Selected Examples):</strong>
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<strong>.0001 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 63</strong>
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CPLX1, GLU108TER
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SNP: rs1060499735,
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ClinVar: RCV000454222, RCV000627075
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<p>In 2 sisters (patients BAB6167 and BAB6168), born of consanguineous parents (family HOU2319) with developmental and epileptic encephalopathy-63 (DEE63; 617976), Karaca et al. (2015) identified a homozygous c.322G-T transversion (c.322G-T, NM_006651) in the CPLX1 gene, resulting in a glu108-to-ter (E108X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed, but Karaca et al. (2015) noted that the CPLX1 gene is involved in modulating presynaptic neurotransmitter release. The family was part of a cohort of 128 mostly consanguineous families with neurogenetic disorders, often including brain malformations, that underwent whole-exome sequencing. </p>
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<strong>.0002 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 63</strong>
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CPLX1, CYS105TER
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SNP: rs1553851860,
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ClinVar: RCV000627076
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<p>In 2 sisters, born of consanguineous Lebanese parents, with developmental and epileptic encephalopathy-63 (DEE63; 617976), Redler et al. (2017) identified a homozygous c.315C-A transversion (c.315C-A, NM_006651.2) in exon 4 of the CPLX1 gene, resulting in a cys105-to-ter (C105X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. The patients had onset of intractable infantile spasms and myoclonic epilepsy in the first weeks to months of life. </p>
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<span class="mim-font">
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<strong>.0003 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 63</strong>
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CPLX1, LEU128MET ({dbSNP rs371709824})
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SNP: rs371709824,
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gnomAD: rs371709824,
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ClinVar: RCV000627077, RCV001320840
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<p>In a boy (patient 3), born of consanguineous parents originating from the Turkmen population, with developmental and epileptic encephalopathy-63 (DEE63; 617976), Redler et al. (2017) identified a homozygous c.382C-A transversion (c.382C-A, NM_006651.2) in exon 4 of the CPLX1 gene, resulting in a leu128-to-met (L128M) substitution at a highly conserved residue in the C-terminal domain in a region important for synaptic vesicle binding. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was present in heterozygous state in 6 of 33,197 individuals in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. The patient had onset of refractory myoclonic seizures at 2 years of age. </p>
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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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<p class="mim-text-font">
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Drew, C. J. G., Kyd, R. J., Morton, A. J.
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<strong>Complexin 1 knockout mice exhibit marked deficits in social behaviours but appear to be cognitively normal.</strong>
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Hum. Molec. Genet. 16: 2288-2305, 2007.
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[PubMed: 17652102]
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[Full Text: https://doi.org/10.1093/hmg/ddm181]
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<p class="mim-text-font">
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Giraudo, C. G., Eng, W. S., Melia, T. J., Rothman, J. E.
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<strong>A clamping mechanism involved in SNARE-dependent exocytosis.</strong>
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Science 313: 676-680, 2006.
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[PubMed: 16794037]
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[Full Text: https://doi.org/10.1126/science.1129450]
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<li>
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<p class="mim-text-font">
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Giraudo, C. G., Garcia-Diaz, A., Eng, W. S., Chen, Y., Hendrickson, W. A., Melia, T. J., Rothman, J. E.
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<strong>Alternative zippering as an on-off switch for SNARE-mediated fusion.</strong>
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Science 323: 512-516, 2009.
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[PubMed: 19164750]
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[Full Text: https://doi.org/10.1126/science.1166500]
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<li>
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<p class="mim-text-font">
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Glynn, D., Drew, C. J., Reim, K., Brose, N., Morton, A. J.
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<strong>Profound ataxia in complexin I knockout mice masks a complex phenotype that includes exploratory and habituation deficits.</strong>
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Hum. Molec. Genet. 14: 2369-2385, 2005.
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[PubMed: 16000319]
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[Full Text: https://doi.org/10.1093/hmg/ddi239]
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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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Karaca, E., Harel, T., Pehlivan, D., Jhangiani, S. N., Gambin, T., Akdemir, Z. C., Gonzaga-Jauregui, C., Erdin, S., Bayram, Y., Campbell, I. M., Hunter, J. V., Atik, M. M., and 52 others.
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<strong>Genes that affect brain structure and function identified by rare variant analyses of mendelian neurologic disease.</strong>
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Neuron 88: 499-513, 2015.
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[PubMed: 26539891]
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[Full Text: https://doi.org/10.1016/j.neuron.2015.09.048]
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</li>
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<li>
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<p class="mim-text-font">
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Maximov, A., Tang, J., Yang, X., Pang, Z. P., Sudhof, T. C.
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<strong>Complexin controls the force transfer from SNARE complexes to membranes in fusion.</strong>
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Science 323: 516-521, 2009.
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[PubMed: 19164751]
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[Full Text: https://doi.org/10.1126/science.1166505]
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<p class="mim-text-font">
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McMahon, H. T., Missler, M., Li, C., Sudhof, T. C.
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<strong>Complexins: cytosolic proteins that regulate SNAP receptor function.</strong>
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Cell 83: 111-119, 1995.
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[PubMed: 7553862]
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[Full Text: https://doi.org/10.1016/0092-8674(95)90239-2]
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</p>
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<li>
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<p class="mim-text-font">
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Redler, S., Strom, T. M., Wieland, T., Cremer, K., Engels, H., Distelmaier, F., Schaper, J., Kuchler, A., Lemke, J. R., Jeschke, S., Schreyer, N., Sticht, H., Koch, M., Ludecke, H.-J., Wieczorek, D.
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<strong>Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID.</strong>
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Europ. J. Hum. Genet. 25: 889-893, 2017.
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[PubMed: 28422131]
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[Full Text: https://doi.org/10.1038/ejhg.2017.52]
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Reim, K., Mansour, M., Varoqueaux, F., McMahon, H. T., Sudhof, T. C., Brose, N., Rosenmund, C.
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<strong>Complexins regulate a late step in Ca(2+)-dependent neurotransmitter release.</strong>
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Cell 104: 71-81, 2001.
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[PubMed: 11163241]
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[Full Text: https://doi.org/10.1016/s0092-8674(01)00192-1]
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Tang, J., Maximov, A., Shin, O.-H., Dai, H., Rizo, J., Sudhof, T. C.
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<strong>A complexin/synaptotagmin 1 switch controls fast synaptic vesicle exocytosis.</strong>
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Cell 126: 1175-1187, 2006.
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[PubMed: 16990140]
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[Full Text: https://doi.org/10.1016/j.cell.2006.08.030]
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Tokumaru, H., Umayahara, K., Pellegrini, L. L., Ishizuka, T., Saisu, H., Betz, H., Augustine, G. J., Abe, T.
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<strong>SNARE complex oligomerization by synaphin/complexin is essential for synaptic vesicle exocytosis.</strong>
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Cell 104: 421-432, 2001.
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[PubMed: 11239399]
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[Full Text: https://doi.org/10.1016/s0092-8674(01)00229-x]
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Contributors:
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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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Cassandra L. Kniffin - updated : 05/14/2018<br>Cassandra L. Kniffin - updated : 9/2/2009<br>Patricia A. Hartz - updated : 2/4/2009<br>George E. Tiller - updated : 1/12/2009<br>Paul J. Converse - updated : 12/22/2006<br>Ada Hamosh - updated : 9/6/2006<br>Stylianos E. Antonarakis - updated : 3/8/2001<br>Stylianos E. Antonarakis - updated : 2/1/2001
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<span class="mim-text-font">
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Paul J. Converse : 6/6/2000
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Edit History:
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carol : 06/27/2024<br>alopez : 11/17/2020<br>joanna : 11/04/2020<br>carol : 05/16/2018<br>carol : 05/15/2018<br>ckniffin : 05/14/2018<br>wwang : 09/09/2009<br>ckniffin : 9/2/2009<br>mgross : 2/5/2009<br>mgross : 2/5/2009<br>terry : 2/4/2009<br>wwang : 1/12/2009<br>mgross : 1/2/2007<br>terry : 12/22/2006<br>alopez : 9/11/2006<br>alopez : 9/11/2006<br>terry : 9/6/2006<br>mgross : 12/12/2001<br>mgross : 3/8/2001<br>mgross : 2/1/2001<br>mgross : 6/7/2000<br>mgross : 6/6/2000<br>mgross : 6/6/2000
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