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Entry
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- *600514 - REELIN; RELN
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600514</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 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 role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cytogenetics">Cytogenetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<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" style="margin-left: 1em">
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<a href="#history">History</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/600514">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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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000189056;t=ENST00000428762" 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=5649" 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=600514" 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=ENSG00000189056;t=ENST00000428762" 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_005045,NM_173054" 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_005045" 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=600514" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=02742&isoform_id=02742_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/RELN" 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/1743885,4760438,21358753,21464487,27436938,27436940,30172687,30172691,30172715,37674409,41393494,51095167,51095168,119603742,119603743,119603744,194375824,194387032,296452988,444738459" 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/P78509" 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=5649" 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=ENSG00000189056;t=ENST00000428762" 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=RELN" 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=RELN" 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+5649" 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/RELN" 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:5649" 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/5649" 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=chr7&hgg_gene=ENST00000428762.6&hgg_start=103471789&hgg_end=103989658&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:9957" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:9957" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/reln" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600514[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=600514[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/RELN/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000189056" 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=RELN" 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=RELN" 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=RELN" 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=RELN&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/PA34323" 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:9957" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:103022" 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/RELN#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:103022" 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/5649/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA001867/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=5649" 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://zfin.org/ZDB-GENE-020822-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<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:5649" 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=RELN&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 717977003<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
600514
|
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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REELIN; RELN
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
RL
|
|
</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=RELN" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">RELN</a></em></strong>
|
|
</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/7/559?start=-3&limit=10&highlight=559">7q22.1</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:103471789-103989658&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'})">7:103,471,789-103,989,658</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=616436,257320" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/7/559?start=-3&limit=10&highlight=559">
|
|
7q22.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Epilepsy, familial temporal lobe, 7}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/616436"> 616436 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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>
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
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|
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|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Lissencephaly 2 (Norman-Roberts type)
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/257320"> 257320 </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>
|
|
|
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<p>The RELN gene encodes reelin, a large secreted glycoprotein that is produced by specific cell types within the developing brain and activates a signaling pathway in postmitotic migrating neurons required for proper positioning of neurons within laminated nervous system parenchyma (summary by <a href="#34" class="mim-tip-reference" title="Zaki, M., Shehab, M., El-Aleem, A. A., Abdel-Salam, G., Koeller, H. B., Ilkin, Y., Ross, M. E., Dobyns, W. B., Gleeson, J. G. <strong>Identification of a novel recessive RELN mutation using a homozygous balanced reciprocal translocation.</strong> Am. J. Med. Genet. 143A: 939-944, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17431900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17431900</a>] [<a href="https://doi.org/10.1002/ajmg.a.31667" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17431900">Zaki et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17431900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The autosomal recessive mouse mutation 'reeler' (rl) leads to impaired motor coordination, tremors, and ataxia. Neurons in affected mice fail to reach their correct locations in the developing brain, disrupting the organization of the cerebellar and cerebral cortices and other laminated regions. <a href="#5" class="mim-tip-reference" title="D'Arcangelo, G., Miao, G. G., Chen, S.-C., Soares, H. D., Morgan, J. I., Curran, T. <strong>A protein related to extracellular matrix proteins deleted in the mouse mutant reeler.</strong> Nature 374: 719-723, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7715726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7715726</a>] [<a href="https://doi.org/10.1038/374719a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7715726">D'Arcangelo et al. (1995)</a> isolated a gene called reelin (Reln) that was deleted in 2 reeler alleles. The allele used in cloning the gene was produced by transgene insertion. Normal but not mutant mice expressed reelin in embryonic and postnatal neurons during periods of neuronal migration. The encoded protein resembled extracellular matrix proteins involved in cell adhesion. <a href="#5" class="mim-tip-reference" title="D'Arcangelo, G., Miao, G. G., Chen, S.-C., Soares, H. D., Morgan, J. I., Curran, T. <strong>A protein related to extracellular matrix proteins deleted in the mouse mutant reeler.</strong> Nature 374: 719-723, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7715726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7715726</a>] [<a href="https://doi.org/10.1038/374719a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7715726">D'Arcangelo et al. (1995)</a> found that the 10,383-bp reelin open reading frame (ORF) begins with a methionine codon preceded by a consensus sequence for translation initiation. The stop codon is followed by about 1 kb of 3-prime untranslated sequence and a potential polyadenylation signal. The ORF encodes a protein of 3,461 amino acids with a relative molecular mass of 388 kD. A single reelin transcript of about 12 kb was detected in RNA from the brains of normal mice, but not from brains of affected mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7715726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Hirotsune, S., Takahara, T., Sasaki, N., Hirose, K., Yoshiki, A., Ohashi, T., Kusakabe, M., Murakami, Y., Muramatsu, M., Watanabe, S., Nakao, K., Katsuki, M., Hayashizaki, Y. <strong>The reeler gene encodes a protein with an EGF-like motif expressed by pioneer neurons.</strong> Nature Genet. 10: 77-83, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7647795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7647795</a>] [<a href="https://doi.org/10.1038/ng0595-77" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7647795">Hirotsune et al. (1995)</a> also identified a strong candidate cDNA for the mouse reeler gene. This 5-kb transcript encoded a 94.4-kD protein consisting of 881 amino acids and possessing 2 EGF-like motifs. They analyzed 2 mutant alleles: 'Jackson reeler,' which was found to have a deletion of the entire gene, and 'Orleans reeler,' which exhibited a 220-bp deletion in the ORF that included the second EGF-like motif and resulted in a frameshift. In situ hybridization demonstrated that the transcript is detected exclusively in the pioneer neurons that guide neuronal cell migration along the radial array. The findings offered an explanation of how the reeler mutant phenotype causes a disturbance of the complex architecture of the neuronal network. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7647795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="DeSilva, U., D'Arcangelo, G., Braden, V. V., Chen, J., Miao, G. G., Curran, T., Green, E. D. <strong>The human reelin gene: isolation, sequencing, and mapping on chromosome 7.</strong> Genome Res. 7: 157-164, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9049633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9049633</a>] [<a href="https://doi.org/10.1101/gr.7.2.157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9049633">DeSilva et al. (1997)</a> found that, like its murine counterpart, human reelin (RELN) is large, encoding an mRNA of approximately 12 kb. The mouse and human proteins, predicted from the ORF of the overlapping cDNA clones, are similar in size (388 kD) and the amino acid and nucleotide sequences are 94.2% and 87.2% identical, respectively. Northern hybridization analysis revealed that RELN is expressed in fetal and postnatal brain as well as in liver. The expression of RELN in postnatal human brain was high in the cerebellum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9049633" 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="#27" class="mim-tip-reference" title="Royaux, I., Lambert de Rouvroit, C., D'Arcangelo, G., Demirov, D., Goffinet, A. M. <strong>Genomic organization of the mouse reelin gene.</strong> Genomics 46: 240-250, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9417911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9417911</a>] [<a href="https://doi.org/10.1006/geno.1997.4983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9417911">Royaux et al. (1997)</a> described the genomic structure of the mouse Reln gene and the 5-prime-flanking genomic DNA sequences. The gene contains 65 exons spanning approximately 450 kb of genomic DNA. They identified different reelin transcripts, formed by alternative splicing of a microexon as well as by use of 2 different polyadenylation sites. All splice sites conform to the GT-AG rule, except for the splice donor site of intron 30, which is GC instead of GT. A processed pseudogene was present in intron 42. Its nucleotide sequence was 86% identical to the sequence of the rat RDJ1 cDNA which codes for a DnaJ-like protein of the Hsp40 family. The genomic structures of the mouse and human RELN genes appear to be highly conserved. The presence of tandemly repeated regions in the reelin protein suggested that gene duplication events occurred during evolution. By comparison of the amino acid sequences of the 8 repeats and the positions of introns, <a href="#27" class="mim-tip-reference" title="Royaux, I., Lambert de Rouvroit, C., D'Arcangelo, G., Demirov, D., Goffinet, A. M. <strong>Genomic organization of the mouse reelin gene.</strong> Genomics 46: 240-250, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9417911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9417911</a>] [<a href="https://doi.org/10.1006/geno.1997.4983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9417911">Royaux et al. (1997)</a> suggested a model for the evolution of the repeat coding portion of the reelin gene from a putative ancestral minigene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9417911" 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>To map the RL gene, <a href="#6" class="mim-tip-reference" title="D'Arcangelo, G. <strong>Personal Communication.</strong> Nutley, N. J. 6/2/1995."None>D'Arcangelo (1995)</a> used a mouse reelin probe to isolate a human cDNA from a cerebellum phage library. A P1 clone was then used for fluorescence in situ hybridization (FISH). The human reelin gene maps to 7q22, a chromosomal region that had not yet been linked to any human genetic disease (<a href="#5" class="mim-tip-reference" title="D'Arcangelo, G., Miao, G. G., Chen, S.-C., Soares, H. D., Morgan, J. I., Curran, T. <strong>A protein related to extracellular matrix proteins deleted in the mouse mutant reeler.</strong> Nature 374: 719-723, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7715726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7715726</a>] [<a href="https://doi.org/10.1038/374719a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7715726">D'Arcangelo et al., 1995</a>). RL was also mapped to YAC contigs spanning the 7q22 region. In the mouse, the rl gene maps to chromosome 5 (<a href="#13" class="mim-tip-reference" title="Green, M. C. <strong>Catalog of mutant genes and polymorphic loci.In: Lyon, M. F.; Searle, A. G. (eds.) : Genetic Variants and Strains of the Laboratory Mouse. (2nd ed.)</strong> Oxford: Oxford Univ. Press (pub.) 1989."None>Green, 1989</a>), which is known to have a long region of homology to human chromosome 7. Based on both FISH and localization within a well-positioned YAC contig, <a href="#10" class="mim-tip-reference" title="DeSilva, U., D'Arcangelo, G., Braden, V. V., Chen, J., Miao, G. G., Curran, T., Green, E. D. <strong>The human reelin gene: isolation, sequencing, and mapping on chromosome 7.</strong> Genome Res. 7: 157-164, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9049633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9049633</a>] [<a href="https://doi.org/10.1101/gr.7.2.157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9049633">DeSilva et al. (1997)</a> mapped the RELN gene to chromosome 7q22. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9049633+7715726" 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="#20" class="mim-tip-reference" title="Impagnatiello, F., Guidotti, A. R., Pesold, C., Dwivedi, Y., Caruncho, H., Pisu, M. G., Uzunov, D. P., Smalheiser, N. R., Davis, J. M., Pandey, G. N., Pappas, G. D., Tueting, P., Sharma, R. P., Costa, E. <strong>A decrease of reelin expression as a putative vulnerability factor in schizophrenia.</strong> Proc. Nat. Acad. Sci. 95: 15718-15723, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9861036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9861036</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9861036[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.26.15718" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9861036">Impagnatiello et al. (1998)</a> suggested that reelin may have a role in schizophrenia (<a href="/entry/181500">181500</a>) because it regulates positioning and/or trophism of cortical pyramidal neurons, interneurons, and Purkinje cells during brain development. Another factor that plays an important role in guiding the migration of embryonic cortical neurons to their final destinations in the subcortical plate is the gene that is mutant in the mouse 'disabled-1' mutation. This gene encodes an adaptor protein (Dab1; <a href="/entry/603448">603448</a>) that is a phosphorylation target for a signaling cascade putatively triggered by the Reln protein interaction with extracellular matrix (ECM) proteins. Dab1 expression is deficient in another neurologic genetic phenotype, the 'scrambler' mouse, which is neurologically and behaviorally similar to the reeler mouse. During ontogenesis of a mammalian brain, including human brain, RELN is abundantly synthesized by the Cajal-Retzius cells and other pioneer neurons located in the telencephalic marginal zone and by granule cells of the external granular layer of the cerebellum. In wildtype and scrambler mice, Reln is secreted into the ECM, but the reeler mouse neither synthesizes nor secretes typical Reln protein. During development, telencephalic migrating neurons and interneurons express DAB1, but they neither express nor secrete RELN. In the reeler mouse, the telencephalic neurons (which are misplaced following migration) express approximately 10-fold more Dab1 than their wildtype counterpart. Such an increase in the expression of a protein that virtually functions as a receptor is expected to occur when the specific signal for the receptor is missing. The function of RELN in embryos may ultimately depend on the phosphorylation of DAB1 expressed selectively in migrating telencephalic pyramidal neurons and cerebellar Purkinje neurons. <a href="#20" class="mim-tip-reference" title="Impagnatiello, F., Guidotti, A. R., Pesold, C., Dwivedi, Y., Caruncho, H., Pisu, M. G., Uzunov, D. P., Smalheiser, N. R., Davis, J. M., Pandey, G. N., Pappas, G. D., Tueting, P., Sharma, R. P., Costa, E. <strong>A decrease of reelin expression as a putative vulnerability factor in schizophrenia.</strong> Proc. Nat. Acad. Sci. 95: 15718-15723, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9861036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9861036</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9861036[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.26.15718" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9861036">Impagnatiello et al. (1998)</a> studied postmortem prefrontal cortices, temporal cortices, hippocampi, caudate nuclei, and cerebella of schizophrenia patients and their matched nonpsychiatric subjects. In all of the brain areas studied, RELN and its mRNA were significantly reduced (approximately 50%) in patients with schizophrenia; this decrease was similar in patients affected by undifferentiated or paranoid schizophrenia. On the other hand, DAB1 was expressed at normal levels in all of these areas that showed a decrease in RELN. The frequency of RELN DNA polymorphism in schizophrenia patients and the location of this variation in a stretch of genomic DNA important for the regulation of RELN protein secretion (<a href="#27" class="mim-tip-reference" title="Royaux, I., Lambert de Rouvroit, C., D'Arcangelo, G., Demirov, D., Goffinet, A. M. <strong>Genomic organization of the mouse reelin gene.</strong> Genomics 46: 240-250, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9417911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9417911</a>] [<a href="https://doi.org/10.1006/geno.1997.4983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9417911">Royaux et al., 1997</a>) increased the clinical interest in RELN gene abnormalities as putative vulnerability factors in schizophrenia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9861036+9417911" 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>Layering of neurons in the cerebral cortex and cerebellum requires RELN and DAB1. By targeted disruption experiments in mice, <a href="#31" class="mim-tip-reference" title="Trommsdorff, M., Gotthardt, M., Hiesberger, T., Shelton, J., Stockinger, W., Nimpf, J., Hammer, R. E., Richardson, J. A., Herz, J. <strong>Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2.</strong> Cell 97: 689-701, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10380922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10380922</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80782-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10380922">Trommsdorff et al. (1999)</a> showed that 2 cell surface receptors, very low density lipoprotein receptor (VLDLR; <a href="/entry/192977">192977</a>) and apolipoprotein E receptor-2 (APOER2; <a href="/entry/602600">602600</a>), are also required. Both receptors bound Dab1 on their cytoplasmic tails and were expressed in cortical and cerebellar layers adjacent to layers expressing Reln. Dab1 expression was upregulated in knockout mice lacking both the Vldlr and Apoer2 genes. Inversion of cortical layers, absence of cerebellar foliation, and the migration of Purkinje cells in these animals precisely mimicked the phenotype of mice lacking Reln or Dab1. These findings established novel signaling functions for the LDL receptor gene family and suggested that VLDLR and APOER2 participate in transmitting the extracellular RELN signal to intracellular signaling processes initiated by DAB1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10380922" 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 in vitro binding experiments, <a href="#15" class="mim-tip-reference" title="Hiesberger, T., Trommsdorff, M., Howell, B. W., Goffinet, A., Mumby, M. C., Cooper, J. A., Herz, J. <strong>Direct binding of reelin to VLDL receptor and apoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation.</strong> Neuron 24: 481-489, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10571241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10571241</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80861-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10571241">Hiesberger et al. (1999)</a> showed that Reln binds directly and specifically to the extracellular domains of Vldlr and ApoER2. In primary embryonic neuron cultures, they demonstrated that blockade of Vldlr and ApoER2 ligand binding correlates with loss of Reelin-induced tyrosine phosphorylation of Dab1. With Western blot analysis, they demonstrated that mice that lack either Reln or Vldlr and ApoER2 (<a href="#31" class="mim-tip-reference" title="Trommsdorff, M., Gotthardt, M., Hiesberger, T., Shelton, J., Stockinger, W., Nimpf, J., Hammer, R. E., Richardson, J. A., Herz, J. <strong>Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2.</strong> Cell 97: 689-701, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10380922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10380922</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80782-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10380922">Trommsdorff et al., 1999</a>) exhibit a dramatic increase in the phosphorylation level of the microtubule-stabilizing protein tau (MAPT; 157140). <a href="#15" class="mim-tip-reference" title="Hiesberger, T., Trommsdorff, M., Howell, B. W., Goffinet, A., Mumby, M. C., Cooper, J. A., Herz, J. <strong>Direct binding of reelin to VLDL receptor and apoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation.</strong> Neuron 24: 481-489, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10571241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10571241</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80861-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10571241">Hiesberger et al. (1999)</a> concluded that Reln acts via Vldlr and ApoER2 to regulate Dab1 tyrosine phosphorylation and microtubule function in neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10380922+10571241" 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="D'Arcangelo, G., Homayouni, R., Keshvara, L., Rice, D. S., Sheldon, M., Curran, T. <strong>Reelin is a ligand for lipoprotein receptors.</strong> Neuron 24: 471-479, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10571240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10571240</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80860-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10571240">D'Arcangelo et al. (1999)</a> transfected 293T cells with expression constructs encoding full-length VLDLR, APOER2, and LDLR (<a href="/entry/606945">606945</a>) cDNA. Cells were incubated in the presence of reelin. By Western blotting, all 3 reelin isoforms (400, 250, and 180 kD) were found to associate with 293T cells expressing VLDLR and APOER2, and to a lower extent with cells expressing LDLR; no binding was detected using mock transfected cells. Binding required calcium and was inhibited in the presence of APOE (<a href="/entry/107741">107741</a>). Furthermore, the CR-50 monoclonal antibody, which inhibits reelin function, blocked the association of reelin with VLDLR. After binding to VLDLR on the cell surface, reelin was internalized into vesicles. In dissociated embryonic cortical neurons, APOE reduced the level of reelin-induced intracellular tyrosine phosphorylation of Dab1. The authors suggested that reelin directs neuronal migration by binding to VLDLR and APOER2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10571240" 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>Mutation of the Reln gene in the mouse disrupts neuronal migration in several brain regions and gives rise to functional deficits, such as ataxic gait and trembling. Thus, reelin is thought to control cell-cell interactions critical for cell positioning in the brain. Although an abundance of reelin transcript is found in the embryonic spinal cord, it was generally thought that neuronal migration in the spinal cord is not affected by reelin. However, <a href="#33" class="mim-tip-reference" title="Yip, J. W., Yip, Y. P. L., Nakajima, K., Capriotti, C. <strong>Reelin controls position of autonomic neurons in the spinal cord.</strong> Proc. Nat. Acad. Sci. 97: 8612-8616, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10880573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10880573</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10880573[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.150040497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10880573">Yip et al. (2000)</a> showed that migration of sympathetic preganglionic neurons in the spinal cord is affected by reelin. This study indicated that reelin affects neuronal migration outside of the brain. Moreover, the relationship between reelin and migrating preganglionic neurons suggests that reelin acts as a barrier to neuronal migration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10880573" 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 neuronal precursors from postnatal mice in a Matrigel culture system, <a href="#14" class="mim-tip-reference" title="Hack, I., Bancila, M., Loulier, K., Carroll, P., Cremer, H. <strong>Reelin is a detachment signal in tangential chain-migration during postnatal neurogenesis.</strong> Nature Neurosci. 5: 939-945, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12244323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12244323</a>] [<a href="https://doi.org/10.1038/nn923" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12244323">Hack et al. (2002)</a> showed that reelin acted as a detachment signal for chain-migrating interneuron precursors in the olfactory bulb, inducing their dispersal into individual cells. In vivo studies of reeler mutant mice showed disrupted organization of the olfactory bulb as well as failure of individual neuronal migration. Reelin did not act as a stop signal, did not provide directional cues, and did not affect migration distance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12244323" 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 in vitro and in vivo migration assays, <a href="#11" class="mim-tip-reference" title="Dulabon, L., Olson, E. C., Taglienti, M. G., Eisenhuth, S., McGrath, B., Walsh, C. A., Kreidberg, J. A., Anton, E. S. <strong>Reelin binds alpha-3-beta-1 integrin and inhibits neuronal migration.</strong> Neuron 27: 33-44, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10939329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10939329</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)00007-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10939329">Dulabon et al. (2000)</a> showed that reelin inhibits migration of cortical neurons in mouse embryonic brain. Immunoprecipitation experiments showed that reelin associates with alpha-3-beta-1 integrin (see <a href="/entry/605025">605025</a> and <a href="/entry/135630">135630</a>), a receptor that mediates neuronal adhesion to radial glial fibers and radial migration. Using alpha-3-beta-1 integrin-deficient mouse embryos for migration assays, <a href="#11" class="mim-tip-reference" title="Dulabon, L., Olson, E. C., Taglienti, M. G., Eisenhuth, S., McGrath, B., Walsh, C. A., Kreidberg, J. A., Anton, E. S. <strong>Reelin binds alpha-3-beta-1 integrin and inhibits neuronal migration.</strong> Neuron 27: 33-44, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10939329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10939329</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)00007-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10939329">Dulabon et al. (2000)</a> showed that deficiency in functional alpha-3-beta-1 integrins leads to deficiency in reelin function. They observed reduced levels of Dab1 protein and elevated expression of a 180-kD reelin fragment in cerebral cortices of alpha-3-beta-1 integrin-deficient mice. <a href="#11" class="mim-tip-reference" title="Dulabon, L., Olson, E. C., Taglienti, M. G., Eisenhuth, S., McGrath, B., Walsh, C. A., Kreidberg, J. A., Anton, E. S. <strong>Reelin binds alpha-3-beta-1 integrin and inhibits neuronal migration.</strong> Neuron 27: 33-44, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10939329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10939329</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)00007-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10939329">Dulabon et al. (2000)</a> concluded that reelin may arrest neuronal migration and promote normal cortical lamination by binding alpha-3-beta-1 integrin and modulating integrin-mediated cellular adhesion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10939329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By examining mice deficient in either Reln or Dab1, <a href="#26" class="mim-tip-reference" title="Rice, D. S., Nusinowitz, S., Azimi, A. M., Martinez, A., Soriano, E., Curran, T. <strong>The reelin pathway modulates the structure and function of retinal synaptic circuitry.</strong> Neuron 31: 929-941, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11580894/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11580894</a>] [<a href="https://doi.org/10.1016/s0896-6273(01)00436-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11580894">Rice et al. (2001)</a> found that expression of both genes was essential for the patterning of synaptic connectivity in the retina. Physiologic studies of mice deficient in either gene detected attenuated rod-driven retinal responses that were associated with a decrease in rod bipolar cell density and an abnormal distribution of processes in the inner plexiform layer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11580894" 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="#12" class="mim-tip-reference" title="Grayson, D. R., Jia, X., Chen, Y., Sharma, R. P., Mitchell, C. P., Guidotti, A., Costa, E. <strong>Reelin promoter hypermethylation in schizophrenia.</strong> Proc. Nat. Acad. Sci. 102: 9341-9346, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15961543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15961543</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15961543[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0503736102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15961543">Grayson et al. (2005)</a> found that postmortem brains from patients with schizophrenia had increased methylation of the RELN gene within the promoter region, particularly at positions -134 and -139, compared to controls. The authors hypothesized that hypermethylation of this promoter region results in decreased expression of RELN in schizophrenia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15961543" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Botella-Lopez, A., Burgaya, F., Gavin, R., Garcia-Ayllon, M. S., Gomez-Tortosa, E., Pena-Casanova, J., Urena, J. M., Del Rio, J. A., Blesa, R., Soriano, E., Saez-Valero, J. <strong>Reelin expression and glycosylation patterns are altered in Alzheimer's disease.</strong> Proc. Nat. Acad. Sci. 103: 5573-5578, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16567613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16567613</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16567613[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0601279103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16567613">Botella-Lopez et al. (2006)</a> found increased levels of a 180-kD reelin fragment in CSF from 19 patients with Alzheimer disease (AD; <a href="/entry/104300">104300</a>) compared to 11 nondemented controls. Western blot and PCR analysis confirmed increased levels of reelin protein and mRNA in tissue samples from the frontal cortex of AD patients. Reelin was not increased in plasma samples, suggesting distinct cellular origins. The reelin 180-kD fragment was also increased in CSF samples of other neurodegenerative disorders, including frontotemporal dementia (<a href="/entry/600274">600274</a>), progressive supranuclear palsy (PSP; <a href="/entry/601104">601104</a>), and Parkinson disease (PD; <a href="/entry/168600">168600</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16567613" 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 overexpression and knockdown studies with cultured rat and mouse hippocampal and cortical neurons, <a href="#22" class="mim-tip-reference" title="Matsuki, T., Matthews, R. T., Cooper, J. A., van der Brug, M. P., Cookson, M. R., Hardy, J. A., Olson, E. C., Howell, B. W. <strong>Reelin and Stk25 have opposing roles in neuronal polarization and dendritic Golgi deployment.</strong> Cell 143: 826-836, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21111240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21111240</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21111240[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.cell.2010.10.029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21111240">Matsuki et al. (2010)</a> found that a signaling pathway containing Stk25 (<a href="/entry/602255">602255</a>), Lkb1 (STK11; <a href="/entry/602216">602216</a>), Strad (STRADA; <a href="/entry/608626">608626</a>), and the Golgi protein Gm130 (GOLGA2; <a href="/entry/602580">602580</a>) promoted Golgi condensation and multiple axon outgrowth while inhibiting Golgi deployment into dendrites and dendritic growth. This signaling pathway acted in opposition to the reelin-Dab1 pathway, which tended to inhibit Golgi condensation and axon outgrowth and favor Golgi deployment into dendrites and dendrite outgrowth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21111240" 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>Thirty percent of all cortical interneurons arise from a relatively novel source within the ventral telencephalon, the caudal ganglionic eminence (CGE) (summary by <a href="#9" class="mim-tip-reference" title="De Marco Garcia, N. V., Karayannis, T., Fishell, G. <strong>Neuronal activity is required for the development of specific cortical interneuron subtypes.</strong> Nature 472: 351-355, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21460837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21460837</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21460837[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/nature09865" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21460837">De Marco Garcia et al., 2011</a>). Owing to their late birth date, these interneurons populate the cortex only after the majority of other interneurons and pyramidal cells are already in place and have started to functionally integrate. <a href="#9" class="mim-tip-reference" title="De Marco Garcia, N. V., Karayannis, T., Fishell, G. <strong>Neuronal activity is required for the development of specific cortical interneuron subtypes.</strong> Nature 472: 351-355, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21460837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21460837</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21460837[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/nature09865" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21460837">De Marco Garcia et al. (2011)</a> demonstrated in mice that for CGE-derived reelin-positive and calretinin (<a href="/entry/114051">114051</a>)-positive, but not vasoactive intestinal peptide (VIP; <a href="/entry/192320">192320</a>)-positive, interneurons, activity is essential before postnatal day 3 for correct migration, and that after postnatal day 3, glutamate-mediated activity controls the development of their axons and dendrites. Furthermore, <a href="#9" class="mim-tip-reference" title="De Marco Garcia, N. V., Karayannis, T., Fishell, G. <strong>Neuronal activity is required for the development of specific cortical interneuron subtypes.</strong> Nature 472: 351-355, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21460837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21460837</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21460837[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/nature09865" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21460837">De Marco Garcia et al. (2011)</a> showed that the engulfment and cell motility-1 gene (Elmo1; <a href="/entry/606420">606420</a>), a target of the transcription factor distal-less homeobox-1 (Dlx1; <a href="/entry/600029">600029</a>), is selectively expressed in reelin-positive and calretinin-positive interneurons and is both necessary and sufficient for activity-dependent interneuron migration. <a href="#9" class="mim-tip-reference" title="De Marco Garcia, N. V., Karayannis, T., Fishell, G. <strong>Neuronal activity is required for the development of specific cortical interneuron subtypes.</strong> Nature 472: 351-355, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21460837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21460837</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21460837[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/nature09865" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21460837">De Marco Garcia et al. (2011)</a> concluded that their findings revealed a selective requirement for activity in shaping the cortical integration of specific neuronal subtypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21460837" 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="#29" class="mim-tip-reference" title="Senturk, A., Pfennig, S., Weiss, A., Burk, K., Acker-Palmer, A. <strong>Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration.</strong> Nature 472: 356-360, 2011. Note: Erratum: Nature 478: 274 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21460838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21460838</a>] [<a href="https://doi.org/10.1038/nature09874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21460838">Senturk et al. (2011)</a> showed that the neuronal guidance cues ephrin B proteins are essential for Reelin signaling during the development of laminated structures in the brain. They showed that ephrin Bs genetically interact with Reelin. Notably, compound mouse mutants (Reln heterozygotes null for either Efnb2 (<a href="/entry/600527">600527</a>) or Efnb3 (<a href="/entry/602297">602297</a>)) and triple Efnb1 (<a href="/entry/300035">300035</a>)/Efnb2/Efnb3 knockouts showed neuronal migration defects that recapitulated the ones observed in the neocortex, hippocampus, and cerebellum of the reeler mouse. Mechanistically, <a href="#29" class="mim-tip-reference" title="Senturk, A., Pfennig, S., Weiss, A., Burk, K., Acker-Palmer, A. <strong>Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration.</strong> Nature 472: 356-360, 2011. Note: Erratum: Nature 478: 274 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21460838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21460838</a>] [<a href="https://doi.org/10.1038/nature09874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21460838">Senturk et al. (2011)</a> showed that Reelin binds to the extracellular domain of ephrin Bs, which associate at the membrane with VLDLR (<a href="/entry/192977">192977</a>) and ApoER2 (<a href="/entry/602600">602600</a>) in neurons. Clustering of ephrin Bs leads to the recruitment and phosphorylation of Dab1 (<a href="/entry/603448">603448</a>) which is necessary for Reelin signaling. Conversely, loss of function of ephrin Bs severely impairs Reelin-induced Dab1 phosphorylation. Importantly, activation of ephrin Bs can rescue the reeler neuronal migration defects in the absence of Reelin protein. <a href="#29" class="mim-tip-reference" title="Senturk, A., Pfennig, S., Weiss, A., Burk, K., Acker-Palmer, A. <strong>Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration.</strong> Nature 472: 356-360, 2011. Note: Erratum: Nature 478: 274 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21460838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21460838</a>] [<a href="https://doi.org/10.1038/nature09874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21460838">Senturk et al. (2011)</a> concluded that their results identified ephrin Bs as essential components of the Reelin receptor/signaling pathway to control neuronal migration during the development of the nervous system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21460838" 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="#30" class="mim-tip-reference" title="Shim, S., Kwan, K. Y., Li, M., Lefebvre, V., Sestan, N. <strong>Cis-regulatory control of corticospinal system development and evolution.</strong> Nature 486: 74-79, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22678282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22678282</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22678282[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/nature11094" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22678282">Shim et al. (2012)</a> showed that SOX4 (<a href="/entry/184430">184430</a>) and SOX11 (<a href="/entry/600898">600898</a>) are crucial in regulating reelin expression and the inside-out pattern of cortical layer formation. This regulation is independent of E4, a conserved nonexonic element required for the specification of corticospinal neuron identity and connectivity, and Fezf2 (<a href="/entry/607414">607414</a>), and probably involves interactions with distinct regulatory elements. Cortex-specific double deletion of Sox4 and Sox11 in mice led to the loss of Fezf2 expression, failed specification of corticospinal neurons and, independent of Fezf2, a reeler-like inversion of layers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22678282" 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 rat brain, <a href="#8" class="mim-tip-reference" title="Dazzo, E., Fanciulli, M., Serioli, E., Minervini, G., Pulitano, P., Binelli, S., Di Bonaventura, C., Luisi, C., Pasini, E., Striano, S., Striano, P., Coppola, G., and 11 others. <strong>Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy.</strong> Am. J. Hum. Genet. 96: 992-1000, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26046367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26046367</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26046367[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2015.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26046367">Dazzo et al. (2015)</a> found that Reln and Lgi1 (<a href="/entry/604619">604619</a>) colocalized in neurons in the temporal cortex and hippocampus, suggesting that they are involved in a common molecular pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26046367" 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="#28" class="mim-tip-reference" title="Segarra, M., Aburto, M. R., Cop, F., Llao-Cid, C., Hartl, R., Damm, M., Bethani, I., Parrilla, M., Husainie, D., Schanzer, A., Schlierbach, H., Acker, T., Mohr, L., Torres-Masjoan, L., Ritter, M., Acker-Palmer, A. <strong>Endothelial Dab1 signaling orchestrates neuro-glia-vessel communication in the central nervous system.</strong> Science 361: eaao2861, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30139844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30139844</a>] [<a href="https://doi.org/10.1126/science.aao2861" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30139844">Segarra et al. (2018)</a> found that the neuronal guidance cue reelin possesses proangiogenic activities that ensure the communication of endothelial cells with the glia to control neuronal migration and the establishment of the blood-brain barrier in the mouse brain. Apoer2 and Dab1 expressed in endothelial cells are required for vascularization of the retina and the cerebral cortex. Deletion of Dab1 in endothelial cells leads to a reduced secretion of laminin-alpha 4 (LAMA4; <a href="/entry/600133">600133</a>) and decreased activation of integrin-beta 1 (ITGB1; <a href="/entry/135630">135630</a>) in glial cells, which in turn control neuronal migration and barrier properties of the neurovascular unit. Thus, <a href="#28" class="mim-tip-reference" title="Segarra, M., Aburto, M. R., Cop, F., Llao-Cid, C., Hartl, R., Damm, M., Bethani, I., Parrilla, M., Husainie, D., Schanzer, A., Schlierbach, H., Acker, T., Mohr, L., Torres-Masjoan, L., Ritter, M., Acker-Palmer, A. <strong>Endothelial Dab1 signaling orchestrates neuro-glia-vessel communication in the central nervous system.</strong> Science 361: eaao2861, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30139844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30139844</a>] [<a href="https://doi.org/10.1126/science.aao2861" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30139844">Segarra et al. (2018)</a> concluded that reelin signaling in the endothelium is an instructive and integrative cue essential for neuro-glia-vascular communication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30139844" 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="#34" class="mim-tip-reference" title="Zaki, M., Shehab, M., El-Aleem, A. A., Abdel-Salam, G., Koeller, H. B., Ilkin, Y., Ross, M. E., Dobyns, W. B., Gleeson, J. G. <strong>Identification of a novel recessive RELN mutation using a homozygous balanced reciprocal translocation.</strong> Am. J. Med. Genet. 143A: 939-944, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17431900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17431900</a>] [<a href="https://doi.org/10.1002/ajmg.a.31667" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17431900">Zaki et al. (2007)</a> reported 2 sibs from a consanguineous Egyptian marriage who had cortical lissencephaly with cerebellar hypoplasia, severe epilepsy, and mental retardation. Karyotype analysis identified a homozygous, apparently balanced reciprocal translocation, t(7;12)(q22;p13), in both children. Further analysis confirmed disruption of the RELN gene at chromosome 7q22.1 and undetectable levels of the protein in both children. The unaffected parents were related as double first cousins were heterozygous for the translocation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17431900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Lissencephaly 2</em></strong></p><p>
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Normal development of the cerebral cortex requires long-range migration of cortical neurons from proliferative regions deep in the brain. Lissencephaly ('smooth brain,' from 'lissos,' meaning 'smooth,' and 'encephalos,' meaning 'brain') is a severe developmental disorder in which neuronal migration is impaired, leading to a thickened cerebral cortex whose normally folded contour is simplified and smooth. <a href="#18" class="mim-tip-reference" title="Hong, S. E., Shugart, Y. Y., Huang, D. T., Al Shahwan, S., Grant, P. E., Hourihane, J. O., Martin, N. D. T., Walsh, C. A. <strong>Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.</strong> Nature Genet. 26: 93-96, 2000. Note: Erratum: Nature Genet. 27: 225 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973257</a>] [<a href="https://doi.org/10.1038/79246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973257">Hong et al. (2000)</a> studied an autosomal recessive form of lissencephaly associated with severe abnormalities of the cerebellum, hippocampus, and brainstem (LIS2; <a href="/entry/257320">257320</a>). They tested for linkage to markers near RELN on chromosome 7 and DAB1 on chromosome 1p32-p31 because mutations in the mouse homologs of these 2 genes cause brain defects in mice that resemble lissencephaly, including hypoplasia of the cerebellum, brainstem abnormalities, and a neuronal migration disorder of the neocortex and hippocampus. In 2 unrelated pedigrees, they found substantial regions of homozygosity in affected children near the RELN gene on chromosome 7q22. In these 2 families, they identified different splice site mutations in the RELN gene (<a href="#0001">600514.0001</a> and <a href="#0002">600514.0002</a>, respectively). The study of these patients pointed to several previously unsuspected functions of reelin in and outside of the brain. Although abnormalities of RELN mRNA had been reported in postmortem brains of humans with schizophrenia (<a href="#20" class="mim-tip-reference" title="Impagnatiello, F., Guidotti, A. R., Pesold, C., Dwivedi, Y., Caruncho, H., Pisu, M. G., Uzunov, D. P., Smalheiser, N. R., Davis, J. M., Pandey, G. N., Pappas, G. D., Tueting, P., Sharma, R. P., Costa, E. <strong>A decrease of reelin expression as a putative vulnerability factor in schizophrenia.</strong> Proc. Nat. Acad. Sci. 95: 15718-15723, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9861036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9861036</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9861036[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.26.15718" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9861036">Impagnatiello et al., 1998</a>), no evidence of schizophrenia was found in individuals with heterozygous or homozygous RELN mutations. On the other hand, one of the lissencephaly patients studied with a muscle biopsy showed evidence of abnormal neuromuscular connectivity (<a href="#19" class="mim-tip-reference" title="Hourihane, J. O., Bennett, C. P., Chaudhuri, R., Robb, S. A., Martin, N. D. T. <strong>A sibship with a neuronal migration defect, cerebellar hypoplasia and congenital lymphedema.</strong> Neuropediatrics 24: 43-46, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7682675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7682675</a>] [<a href="https://doi.org/10.1055/s-2008-1071511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7682675">Hourihane et al., 1993</a>). Moreover, at least 3 patients had persistent lymphedema neonatally, and one showed accumulation of chylous (i.e., fatty) ascites fluid that required peritoneal shunting (<a href="#19" class="mim-tip-reference" title="Hourihane, J. O., Bennett, C. P., Chaudhuri, R., Robb, S. A., Martin, N. D. T. <strong>A sibship with a neuronal migration defect, cerebellar hypoplasia and congenital lymphedema.</strong> Neuropediatrics 24: 43-46, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7682675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7682675</a>] [<a href="https://doi.org/10.1055/s-2008-1071511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7682675">Hourihane et al., 1993</a>). The apparent role for reelin in serum homeostasis may reflect reelin interactions with LDL superfamily receptors outside the brain, as well as in the brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9861036+7682675+10973257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Moroccan girl (patient 1), born to consanguineous parents, with LIS2, <a href="#32" class="mim-tip-reference" title="Valence, S., Garel, C., Barth, M., Toutain, A., Paris, C., Amsallem, D., Barthez, M. A., Mayer, M., Rodriguez, D., Burglen, L. <strong>RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.</strong> Clin. Genet. 90: 545-549, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27000652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27000652</a>] [<a href="https://doi.org/10.1111/cge.12779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27000652">Valence et al. (2016)</a> identified a homozygous splice site mutation in the RELN gene (c.8844-2A-G; <a href="#0007">600514.0007</a>). <a href="#32" class="mim-tip-reference" title="Valence, S., Garel, C., Barth, M., Toutain, A., Paris, C., Amsallem, D., Barthez, M. A., Mayer, M., Rodriguez, D., Burglen, L. <strong>RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.</strong> Clin. Genet. 90: 545-549, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27000652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27000652</a>] [<a href="https://doi.org/10.1111/cge.12779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27000652">Valence et al. (2016)</a> noted that the severity of the patient's neocortical defect, involvement of the cerebellar hemispheres with absent folia, and level of disability were strongly suggestive of a defect in the reelin pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27000652" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Familial Temporal Lobe Epilepsy 7</em></strong></p><p>
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In 7 unrelated families of Italian descent with familial temporal lobe epilepsy-7 (ETL7; <a href="/entry/616436">616436</a>), <a href="#8" class="mim-tip-reference" title="Dazzo, E., Fanciulli, M., Serioli, E., Minervini, G., Pulitano, P., Binelli, S., Di Bonaventura, C., Luisi, C., Pasini, E., Striano, S., Striano, P., Coppola, G., and 11 others. <strong>Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy.</strong> Am. J. Hum. Genet. 96: 992-1000, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26046367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26046367</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26046367[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2015.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26046367">Dazzo et al. (2015)</a> identified 7 different heterozygous missense mutations in the RELN gene (see, e.g., <a href="#0003">600514.0003</a>-<a href="#0006">600514.0006</a>). Mutations in the LGI1 gene (<a href="/entry/604619">604619</a>) had been excluded in these families. RELN mutations in the first 4 families were found by whole-exome sequencing; mutations in the 3 subsequent families were found by parallel sequencing of RELN exons in 11 small families with the disorder. Functional studies of the variants were not performed, but 3-dimensional modeling predicted that the mutations would result in structural defects and protein misfolding, which could lead to degradation of the altered proteins. Affected individuals from 4 families had reduced (up to 50%) serum levels of the main 310-kD reelin isoform compared to controls, which most likely resulted from impaired secretion of the altered proteins from hepatocytes. These findings suggested that the mutations resulted in a loss of function. Overall, RELN mutations occurred in 7 (17.5%) of 40 families studied; mutations were not found in families with mesial temporal lobe epilepsy, suggesting that RELN mutations may specifically cause lateral temporal lobe epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26046367" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between variation in the RELN gene and otosclerosis, see <a href="/entry/166800">166800</a>.</p>
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<p>To investigate Reln function, <a href="#21" class="mim-tip-reference" title="Magdaleno, S., Keshvara, L., Curran, T. <strong>Rescue of ataxia and preplate splitting by ectopic expression of reelin in reeler mice.</strong> Neuron 33: 573-586, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11856531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11856531</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00582-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11856531">Magdaleno et al. (2002)</a> generated transgenic mice using the nestin (NES; <a href="/entry/600915">600915</a>) promoter to drive ectopic expression of Reln in the ventricular zone during early brain development. Ectopic Reln expression in transgenic reelin mice, which lack endogenous Reln expression, induced tyrosine phosphorylation of Dab1 in the ventricular zone. The transgene also rescued some, but not all, of the neuroanatomic and behavioral abnormalities characteristic of the reeler phenotype, including ataxia and the migration of Purkinje cells. <a href="#21" class="mim-tip-reference" title="Magdaleno, S., Keshvara, L., Curran, T. <strong>Rescue of ataxia and preplate splitting by ectopic expression of reelin in reeler mice.</strong> Neuron 33: 573-586, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11856531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11856531</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00582-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11856531">Magdaleno et al. (2002)</a> hypothesized that Reln functions in concert with other positional cues to promote cell-cell interactions that are required for layer formation during development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11856531" 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="Assadi, A. H., Zhang, G., Beffert, U., McNeil, R. S., Renfro, A. L., Niu, S., Quattrocchi, C. C., Antalffy, B. A., Sheldon, M., Armstrong, D. D., Wynshaw-Boris, A., Herz, J., D'Arcangelo, G., Clark, G. D. <strong>Interaction of reelin signaling and Lis1 in brain development.</strong> Nature Genet. 35: 270-276, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14578885/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14578885</a>] [<a href="https://doi.org/10.1038/ng1257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14578885">Assadi et al. (2003)</a> investigated interactions between the reelin signaling pathway and Lis1 in brain development. Compound mutant mice with disruptions in the Reln pathway and heterozygous mutations in the Pafah1b1 gene, which encodes Lis1, had a higher incidence of hydrocephalus and enhanced cortical and hippocampal layering defects. The Dab1 signaling molecule and Lis1 bound in a reelin-induced phosphorylation-dependent manner. These data indicated genetic and biochemical interaction between the reelin signaling pathway and LIS1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14578885" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the mouse ventral spinal cord, <a href="#17" class="mim-tip-reference" title="Hochstim, C., Deneen, B., Lukaszewicz, A., Zhou, Q., Anderson, D. J. <strong>Identification of positionally distinct astrocyte subtypes whose identities are specified by a homeodomain code.</strong> Cell 133: 510-522, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18455991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18455991</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18455991[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.cell.2008.02.046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18455991">Hochstim et al. (2008)</a> identified 3 subtypes of white matter astrocytes with differential gene expression corresponding to position. Astrocytes expressing both Reln and Slit1 (<a href="/entry/603742">603742</a>) were in the ventrolateral domain, those expressing Reln only were at the dorsolateral domain, and those expressing Slit1 only were at the ventromedial domain. The distinct positions of these astrocytes were specified by varying expression of the homeodomain transcription factors Pax6 (<a href="/entry/607108">607108</a>) and Nkx6.1 (<a href="/entry/602563">602563</a>). The findings indicated that positional identity is an organizing principle underlying phenotypic diversity among white matter astrocytes, as well as among neurons, and that this diversity is prespecified within precursor cells in the germinal zone of the CNS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18455991" 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="#23" class="mim-tip-reference" title="Miller, C. A., Sweatt, J. D. <strong>Covalent modification of DNA regulates memory formation.</strong> Neuron 53: 857-869, 2007. Note: Erratum: Neuron 59: 1051 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17359920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17359920</a>] [<a href="https://doi.org/10.1016/j.neuron.2007.02.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17359920">Miller and Sweatt (2007)</a> found that DNA methylation, which is mediated by DNA methyltransferase, was dynamically regulated during learning and memory consolidation in adult rats. Animals exposed to an associative context plus shock showed increased Dnmt3a (<a href="/entry/602769">602769</a>) and Dnmt3b (<a href="/entry/602900">602900</a>) mRNA in hippocampal area CA1 compared to context-only animals. Context plus shock rats showed increased methylation and decreased mRNA of the memory suppressor gene PP1C-beta (PPP1CB; <a href="/entry/600590">600590</a>) compared to shock-only controls, as well as increased demethylation and increased mRNA levels of reelin, which is involved in synaptic plasticity, compared to controls. The methylation levels of both these target genes returned to baseline within a day, indicating rapid and dynamic changes. Treatment with a DNMT inhibitor blocked the methylation changes and prevented memory consolidation of fear-conditioned learning, but the memory changes were plastic, and memory consolidation was reestablished after the inhibitor wore off. <a href="#23" class="mim-tip-reference" title="Miller, C. A., Sweatt, J. D. <strong>Covalent modification of DNA regulates memory formation.</strong> Neuron 53: 857-869, 2007. Note: Erratum: Neuron 59: 1051 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17359920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17359920</a>] [<a href="https://doi.org/10.1016/j.neuron.2007.02.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17359920">Miller and Sweatt (2007)</a> noted that DNA methylation has been viewed as having an exclusive role in development, but they emphasized that their findings indicated that rapid and dynamic alteration of DNA methylation can occur in the adult central nervous system in response to environmental stimuli during associative learning in the hippocampus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17359920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 3 children, born of consanguineous Saudi Arabian parents, with lissencephaly-2 (LIS2; <a href="/entry/257320">257320</a>), <a href="#18" class="mim-tip-reference" title="Hong, S. E., Shugart, Y. Y., Huang, D. T., Al Shahwan, S., Grant, P. E., Hourihane, J. O., Martin, N. D. T., Walsh, C. A. <strong>Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.</strong> Nature Genet. 26: 93-96, 2000. Note: Erratum: Nature Genet. 27: 225 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973257</a>] [<a href="https://doi.org/10.1038/79246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973257">Hong et al. (2000)</a> identified a homozygous splice acceptor site mutation in the RELN gene: IVS37AS, G-A, -1. The parents were heterozygous for the mutation. In their article, <a href="#18" class="mim-tip-reference" title="Hong, S. E., Shugart, Y. Y., Huang, D. T., Al Shahwan, S., Grant, P. E., Hourihane, J. O., Martin, N. D. T., Walsh, C. A. <strong>Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.</strong> Nature Genet. 26: 93-96, 2000. Note: Erratum: Nature Genet. 27: 225 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973257</a>] [<a href="https://doi.org/10.1038/79246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973257">Hong et al. (2000)</a> referred to this mutation as IVS36AS, G-A, -1; however, in an erratum, they noted that their system for exon numbering differed from that adopted in the mouse and clarified the human-mouse comparison so that a single numbering system could be used in both species. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10973257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a British family in which the parents were related as half first cousins, <a href="#18" class="mim-tip-reference" title="Hong, S. E., Shugart, Y. Y., Huang, D. T., Al Shahwan, S., Grant, P. E., Hourihane, J. O., Martin, N. D. T., Walsh, C. A. <strong>Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.</strong> Nature Genet. 26: 93-96, 2000. Note: Erratum: Nature Genet. 27: 225 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973257</a>] [<a href="https://doi.org/10.1038/79246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973257">Hong et al. (2000)</a> identified a homozygous 148-bp deletion in the RELN gene, corresponding to the removal of exon 42 (EX42DEL), in 3 brothers, including a set of identical twins, with lissencephaly-2 (LIS2; <a href="/entry/257320">257320</a>). The family had previously been reported by <a href="#19" class="mim-tip-reference" title="Hourihane, J. O., Bennett, C. P., Chaudhuri, R., Robb, S. A., Martin, N. D. T. <strong>A sibship with a neuronal migration defect, cerebellar hypoplasia and congenital lymphedema.</strong> Neuropediatrics 24: 43-46, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7682675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7682675</a>] [<a href="https://doi.org/10.1055/s-2008-1071511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7682675">Hourihane et al. (1993)</a>. At birth, the children showed normal head size, congenital lymphedema, and hypotonia. Brain MRI showed moderate lissencephaly and profound cerebellar hypoplasia. Cognitive development was delayed for all affected children, with little or no language and no ability to sit or stand unsupported. There was also myopia, nystagmus, and generalized seizures that could be controlled with medication. In 1 brother, muscle biopsy showed evidence of abnormal neuromuscular connectivity. One brother showed accumulation of chylous (that is, fatty) ascites fluid that required peritoneal shunting. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7682675+10973257" 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">rs794727996 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794727996;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=rs794727996" 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=rs794727996" 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=RCV000180785" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000180785" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000180785</a>
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<p>In an Italian family (F31) with familial temporal lobe epilepsy-7 (ETL7; <a href="/entry/616436">616436</a>), <a href="#8" class="mim-tip-reference" title="Dazzo, E., Fanciulli, M., Serioli, E., Minervini, G., Pulitano, P., Binelli, S., Di Bonaventura, C., Luisi, C., Pasini, E., Striano, S., Striano, P., Coppola, G., and 11 others. <strong>Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy.</strong> Am. J. Hum. Genet. 96: 992-1000, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26046367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26046367</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26046367[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2015.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26046367">Dazzo et al. (2015)</a> identified a heterozygous c.2392C-A transversion (c.2392C-A, NM_005045.3) in the RELN gene, resulting in a his798-to-asn (H798N) substitution at a highly conserved residue in the Asp-box-2 domain. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project or Exome Variant Server databases, or in 270 controls. A 3-dimensional structural model predicted that the mutation would have a deleterious effect on the organization of reelin repeats. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26046367" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs794727997 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794727997;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/rs794727997?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=rs794727997" 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=rs794727997" 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=RCV000180786" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000180786" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000180786</a>
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<p>In an Italian family (F14) with familial temporal lobe epilepsy-7 (ETL7; <a href="/entry/616436">616436</a>), <a href="#8" class="mim-tip-reference" title="Dazzo, E., Fanciulli, M., Serioli, E., Minervini, G., Pulitano, P., Binelli, S., Di Bonaventura, C., Luisi, C., Pasini, E., Striano, S., Striano, P., Coppola, G., and 11 others. <strong>Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy.</strong> Am. J. Hum. Genet. 96: 992-1000, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26046367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26046367</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26046367[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2015.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26046367">Dazzo et al. (2015)</a> identified a heterozygous c.8347G-T transversion (c.8347G-T, NM_005045.3) in the RELN gene, resulting in a gly2783-to-cys (G2783C) substitution at a highly conserved residue in the Asp-box-13 domain. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project or Exome Variant Server databases, or in 270 controls. A 3-dimensional structural model predicted that the mutation would have a deleterious effect on the organization of reelin repeats. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26046367" 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">rs794727998 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794727998;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=rs794727998" 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=rs794727998" 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=RCV000180787" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000180787" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000180787</a>
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<p>In 2 members of a family (FIA) with familial temporal lobe epilepsy-7 (ETL7; <a href="/entry/616436">616436</a>), <a href="#8" class="mim-tip-reference" title="Dazzo, E., Fanciulli, M., Serioli, E., Minervini, G., Pulitano, P., Binelli, S., Di Bonaventura, C., Luisi, C., Pasini, E., Striano, S., Striano, P., Coppola, G., and 11 others. <strong>Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy.</strong> Am. J. Hum. Genet. 96: 992-1000, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26046367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26046367</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26046367[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2015.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26046367">Dazzo et al. (2015)</a> identified a heterozygous c.2288A-G transition (c.2288A-G, NM_005045.3) in the RELN gene, resulting in an asp763-to-gly (D763G) substitution at a highly conserved residue in repeat 1. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project or Exome Variant Server databases, or in 270 controls. A 3-dimensional structural model predicted that the mutation would perturb the horseshoe-like arrangement of repeat 1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26046367" 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">rs794727999 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794727999;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=rs794727999" 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=rs794727999" 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=RCV000180788" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000180788" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000180788</a>
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<p>In 2 sisters (family PAC) with familial temporal lobe epilepsy-7 (ETL7; <a href="/entry/616436">616436</a>), <a href="#8" class="mim-tip-reference" title="Dazzo, E., Fanciulli, M., Serioli, E., Minervini, G., Pulitano, P., Binelli, S., Di Bonaventura, C., Luisi, C., Pasini, E., Striano, S., Striano, P., Coppola, G., and 11 others. <strong>Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy.</strong> Am. J. Hum. Genet. 96: 992-1000, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26046367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26046367</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26046367[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2015.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26046367">Dazzo et al. (2015)</a> identified a heterozygous c.9526G-A transition (c.9526G-A, NM_005045.3) in the RELN gene, resulting in a glu3176-to-lys (E3176K) substitution at a highly conserved residue in repeat 8. The mutation, which was found by direct sequencing of RELN exons in 11 families with the disorder, was not found in the 1000 Genomes Project or Exome Variant Server databases, or in 270 controls. A 3-dimensional structural model predicted that the mutation would disrupt a structurally important interaction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26046367" 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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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003325325" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003325325" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003325325</a>
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<p>In a Moroccan girl (patient 1), born to consanguineous parents, with lissencephaly-2 (LIS2; <a href="/entry/257320">257320</a>), <a href="#32" class="mim-tip-reference" title="Valence, S., Garel, C., Barth, M., Toutain, A., Paris, C., Amsallem, D., Barthez, M. A., Mayer, M., Rodriguez, D., Burglen, L. <strong>RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.</strong> Clin. Genet. 90: 545-549, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27000652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27000652</a>] [<a href="https://doi.org/10.1111/cge.12779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27000652">Valence et al. (2016)</a> identified homozygosity for a c.8844-2A-G transition in the RELN gene, predicted to result in abnormal splicing and skipping of exon 54, leading to premature termination of translation. The mutation was identified by sequencing of the RELN gene. The parents were not tested for the mutation. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27000652" 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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[<a href="https://doi.org/10.1016/j.cell.2008.02.046" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1055/s-2008-1071511" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0896-6273(02)00582-2" target="_blank">Full Text</a>]
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Yip, J. W., Yip, Y. P. L., Nakajima, K., Capriotti, C.
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<strong>Reelin controls position of autonomic neurons in the spinal cord.</strong>
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Proc. Nat. Acad. Sci. 97: 8612-8616, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10880573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10880573</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10880573[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=10880573" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.150040497" target="_blank">Full Text</a>]
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</p>
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</li>
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<li>
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<a id="34" class="mim-anchor"></a>
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<a id="Zaki2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zaki, M., Shehab, M., El-Aleem, A. A., Abdel-Salam, G., Koeller, H. B., Ilkin, Y., Ross, M. E., Dobyns, W. B., Gleeson, J. G.
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<strong>Identification of a novel recessive RELN mutation using a homozygous balanced reciprocal translocation.</strong>
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Am. J. Med. Genet. 143A: 939-944, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17431900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17431900</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17431900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31667" target="_blank">Full Text</a>]
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<a id="contributors" class="mim-anchor"></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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Hilary J. Vernon - updated : 08/30/2023
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Ada Hamosh - updated : 11/20/2018<br>Cassandra L. Kniffin - updated : 6/24/2015<br>Ada Hamosh - updated : 7/17/2012<br>Ada Hamosh - updated : 7/8/2011<br>Patricia A. Hartz - updated : 2/10/2011<br>Marla J. F. O'Neill - updated : 4/13/2009<br>Cassandra L. Kniffin - updated : 5/15/2008<br>Cassandra L. Kniffin - updated : 7/18/2007<br>Cassandra L. Kniffin - updated : 5/24/2006<br>Patricia A. Hartz - updated : 12/7/2005<br>Cassandra L. Kniffin - updated : 7/11/2005<br>Ada Hamosh - updated : 4/7/2004<br>Victor A. McKusick - updated : 10/31/2003<br>Ada Hamosh - updated : 8/12/2003<br>Dawn Watkins-Chow - updated : 10/31/2002<br>Cassandra L. Kniffin - updated : 9/16/2002<br>Dawn Watkins-Chow - updated : 6/13/2002<br>Dawn Watkins-Chow - updated : 11/25/2001<br>Victor A. McKusick - updated : 9/27/2000<br>Victor A. McKusick - updated : 8/29/2000<br>Wilson H. Y. Lo - updated : 4/6/2000<br>Stylianos E. Antonarakis - updated : 7/8/1999<br>Victor A. McKusick - updated : 3/1/1999<br>Victor A. McKusick - updated : 4/8/1997
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 5/4/1995
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </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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carol : 09/27/2023
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 09/27/2023<br>carol : 08/30/2023<br>carol : 10/14/2021<br>alopez : 11/20/2018<br>carol : 07/09/2016<br>carol : 6/25/2015<br>mcolton : 6/25/2015<br>mcolton : 6/25/2015<br>ckniffin : 6/24/2015<br>alopez : 4/8/2014<br>alopez : 7/17/2012<br>carol : 5/24/2012<br>alopez : 11/29/2011<br>alopez : 7/12/2011<br>terry : 7/8/2011<br>carol : 6/2/2011<br>mgross : 2/16/2011<br>terry : 2/10/2011<br>alopez : 1/10/2011<br>carol : 11/15/2010<br>carol : 11/11/2010<br>wwang : 1/13/2010<br>wwang : 1/13/2010<br>wwang : 4/14/2009<br>terry : 4/13/2009<br>carol : 7/8/2008<br>wwang : 6/16/2008<br>ckniffin : 5/15/2008<br>wwang : 7/19/2007<br>ckniffin : 7/18/2007<br>wwang : 5/25/2006<br>ckniffin : 5/24/2006<br>wwang : 12/15/2005<br>wwang : 12/7/2005<br>wwang : 7/28/2005<br>ckniffin : 7/11/2005<br>terry : 6/3/2004<br>alopez : 4/8/2004<br>terry : 4/7/2004<br>tkritzer : 11/3/2003<br>terry : 10/31/2003<br>mgross : 8/12/2003<br>terry : 8/12/2003<br>carol : 11/4/2002<br>tkritzer : 10/31/2002<br>tkritzer : 10/31/2002<br>alopez : 10/18/2002<br>carol : 9/16/2002<br>carol : 9/16/2002<br>ckniffin : 9/16/2002<br>cwells : 6/13/2002<br>ckniffin : 6/5/2002<br>carol : 11/25/2001<br>carol : 3/13/2001<br>alopez : 1/29/2001<br>mcapotos : 10/13/2000<br>mcapotos : 10/10/2000<br>terry : 9/27/2000<br>alopez : 8/31/2000<br>terry : 8/29/2000<br>carol : 4/7/2000<br>terry : 4/6/2000<br>mgross : 7/8/1999<br>mgross : 7/8/1999<br>carol : 3/22/1999<br>terry : 3/1/1999<br>terry : 3/1/1999<br>terry : 3/1/1999<br>alopez : 1/19/1999<br>carol : 8/12/1998<br>mark : 7/22/1997<br>mark : 4/8/1997<br>terry : 4/2/1997<br>mark : 6/29/1995<br>mark : 5/23/1995<br>mark : 5/4/1995
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<span class="mim-font">
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<strong>*</strong> 600514
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<h3>
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REELIN; RELN
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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RL
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: RELN</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 717977003;
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<strong>
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<em>
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Cytogenetic location: 7q22.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:103,471,789-103,989,658 </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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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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<th>
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Inheritance
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<th>
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Phenotype <br /> mapping key
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<td rowspan="2">
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<span class="mim-font">
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7q22.1
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<td>
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<span class="mim-font">
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{Epilepsy, familial temporal lobe, 7}
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</td>
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<td>
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<span class="mim-font">
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616436
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<td>
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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Lissencephaly 2 (Norman-Roberts type)
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</td>
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<td>
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<span class="mim-font">
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257320
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</table>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The RELN gene encodes reelin, a large secreted glycoprotein that is produced by specific cell types within the developing brain and activates a signaling pathway in postmitotic migrating neurons required for proper positioning of neurons within laminated nervous system parenchyma (summary by Zaki et al., 2007). </p>
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</span>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>The autosomal recessive mouse mutation 'reeler' (rl) leads to impaired motor coordination, tremors, and ataxia. Neurons in affected mice fail to reach their correct locations in the developing brain, disrupting the organization of the cerebellar and cerebral cortices and other laminated regions. D'Arcangelo et al. (1995) isolated a gene called reelin (Reln) that was deleted in 2 reeler alleles. The allele used in cloning the gene was produced by transgene insertion. Normal but not mutant mice expressed reelin in embryonic and postnatal neurons during periods of neuronal migration. The encoded protein resembled extracellular matrix proteins involved in cell adhesion. D'Arcangelo et al. (1995) found that the 10,383-bp reelin open reading frame (ORF) begins with a methionine codon preceded by a consensus sequence for translation initiation. The stop codon is followed by about 1 kb of 3-prime untranslated sequence and a potential polyadenylation signal. The ORF encodes a protein of 3,461 amino acids with a relative molecular mass of 388 kD. A single reelin transcript of about 12 kb was detected in RNA from the brains of normal mice, but not from brains of affected mice. </p><p>Hirotsune et al. (1995) also identified a strong candidate cDNA for the mouse reeler gene. This 5-kb transcript encoded a 94.4-kD protein consisting of 881 amino acids and possessing 2 EGF-like motifs. They analyzed 2 mutant alleles: 'Jackson reeler,' which was found to have a deletion of the entire gene, and 'Orleans reeler,' which exhibited a 220-bp deletion in the ORF that included the second EGF-like motif and resulted in a frameshift. In situ hybridization demonstrated that the transcript is detected exclusively in the pioneer neurons that guide neuronal cell migration along the radial array. The findings offered an explanation of how the reeler mutant phenotype causes a disturbance of the complex architecture of the neuronal network. </p><p>DeSilva et al. (1997) found that, like its murine counterpart, human reelin (RELN) is large, encoding an mRNA of approximately 12 kb. The mouse and human proteins, predicted from the ORF of the overlapping cDNA clones, are similar in size (388 kD) and the amino acid and nucleotide sequences are 94.2% and 87.2% identical, respectively. Northern hybridization analysis revealed that RELN is expressed in fetal and postnatal brain as well as in liver. The expression of RELN in postnatal human brain was high in the cerebellum. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Royaux et al. (1997) described the genomic structure of the mouse Reln gene and the 5-prime-flanking genomic DNA sequences. The gene contains 65 exons spanning approximately 450 kb of genomic DNA. They identified different reelin transcripts, formed by alternative splicing of a microexon as well as by use of 2 different polyadenylation sites. All splice sites conform to the GT-AG rule, except for the splice donor site of intron 30, which is GC instead of GT. A processed pseudogene was present in intron 42. Its nucleotide sequence was 86% identical to the sequence of the rat RDJ1 cDNA which codes for a DnaJ-like protein of the Hsp40 family. The genomic structures of the mouse and human RELN genes appear to be highly conserved. The presence of tandemly repeated regions in the reelin protein suggested that gene duplication events occurred during evolution. By comparison of the amino acid sequences of the 8 repeats and the positions of introns, Royaux et al. (1997) suggested a model for the evolution of the repeat coding portion of the reelin gene from a putative ancestral minigene. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
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<p>To map the RL gene, D'Arcangelo (1995) used a mouse reelin probe to isolate a human cDNA from a cerebellum phage library. A P1 clone was then used for fluorescence in situ hybridization (FISH). The human reelin gene maps to 7q22, a chromosomal region that had not yet been linked to any human genetic disease (D'Arcangelo et al., 1995). RL was also mapped to YAC contigs spanning the 7q22 region. In the mouse, the rl gene maps to chromosome 5 (Green, 1989), which is known to have a long region of homology to human chromosome 7. Based on both FISH and localization within a well-positioned YAC contig, DeSilva et al. (1997) mapped the RELN gene to chromosome 7q22. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Impagnatiello et al. (1998) suggested that reelin may have a role in schizophrenia (181500) because it regulates positioning and/or trophism of cortical pyramidal neurons, interneurons, and Purkinje cells during brain development. Another factor that plays an important role in guiding the migration of embryonic cortical neurons to their final destinations in the subcortical plate is the gene that is mutant in the mouse 'disabled-1' mutation. This gene encodes an adaptor protein (Dab1; 603448) that is a phosphorylation target for a signaling cascade putatively triggered by the Reln protein interaction with extracellular matrix (ECM) proteins. Dab1 expression is deficient in another neurologic genetic phenotype, the 'scrambler' mouse, which is neurologically and behaviorally similar to the reeler mouse. During ontogenesis of a mammalian brain, including human brain, RELN is abundantly synthesized by the Cajal-Retzius cells and other pioneer neurons located in the telencephalic marginal zone and by granule cells of the external granular layer of the cerebellum. In wildtype and scrambler mice, Reln is secreted into the ECM, but the reeler mouse neither synthesizes nor secretes typical Reln protein. During development, telencephalic migrating neurons and interneurons express DAB1, but they neither express nor secrete RELN. In the reeler mouse, the telencephalic neurons (which are misplaced following migration) express approximately 10-fold more Dab1 than their wildtype counterpart. Such an increase in the expression of a protein that virtually functions as a receptor is expected to occur when the specific signal for the receptor is missing. The function of RELN in embryos may ultimately depend on the phosphorylation of DAB1 expressed selectively in migrating telencephalic pyramidal neurons and cerebellar Purkinje neurons. Impagnatiello et al. (1998) studied postmortem prefrontal cortices, temporal cortices, hippocampi, caudate nuclei, and cerebella of schizophrenia patients and their matched nonpsychiatric subjects. In all of the brain areas studied, RELN and its mRNA were significantly reduced (approximately 50%) in patients with schizophrenia; this decrease was similar in patients affected by undifferentiated or paranoid schizophrenia. On the other hand, DAB1 was expressed at normal levels in all of these areas that showed a decrease in RELN. The frequency of RELN DNA polymorphism in schizophrenia patients and the location of this variation in a stretch of genomic DNA important for the regulation of RELN protein secretion (Royaux et al., 1997) increased the clinical interest in RELN gene abnormalities as putative vulnerability factors in schizophrenia. </p><p>Layering of neurons in the cerebral cortex and cerebellum requires RELN and DAB1. By targeted disruption experiments in mice, Trommsdorff et al. (1999) showed that 2 cell surface receptors, very low density lipoprotein receptor (VLDLR; 192977) and apolipoprotein E receptor-2 (APOER2; 602600), are also required. Both receptors bound Dab1 on their cytoplasmic tails and were expressed in cortical and cerebellar layers adjacent to layers expressing Reln. Dab1 expression was upregulated in knockout mice lacking both the Vldlr and Apoer2 genes. Inversion of cortical layers, absence of cerebellar foliation, and the migration of Purkinje cells in these animals precisely mimicked the phenotype of mice lacking Reln or Dab1. These findings established novel signaling functions for the LDL receptor gene family and suggested that VLDLR and APOER2 participate in transmitting the extracellular RELN signal to intracellular signaling processes initiated by DAB1. </p><p>Using in vitro binding experiments, Hiesberger et al. (1999) showed that Reln binds directly and specifically to the extracellular domains of Vldlr and ApoER2. In primary embryonic neuron cultures, they demonstrated that blockade of Vldlr and ApoER2 ligand binding correlates with loss of Reelin-induced tyrosine phosphorylation of Dab1. With Western blot analysis, they demonstrated that mice that lack either Reln or Vldlr and ApoER2 (Trommsdorff et al., 1999) exhibit a dramatic increase in the phosphorylation level of the microtubule-stabilizing protein tau (MAPT; 157140). Hiesberger et al. (1999) concluded that Reln acts via Vldlr and ApoER2 to regulate Dab1 tyrosine phosphorylation and microtubule function in neurons. </p><p>D'Arcangelo et al. (1999) transfected 293T cells with expression constructs encoding full-length VLDLR, APOER2, and LDLR (606945) cDNA. Cells were incubated in the presence of reelin. By Western blotting, all 3 reelin isoforms (400, 250, and 180 kD) were found to associate with 293T cells expressing VLDLR and APOER2, and to a lower extent with cells expressing LDLR; no binding was detected using mock transfected cells. Binding required calcium and was inhibited in the presence of APOE (107741). Furthermore, the CR-50 monoclonal antibody, which inhibits reelin function, blocked the association of reelin with VLDLR. After binding to VLDLR on the cell surface, reelin was internalized into vesicles. In dissociated embryonic cortical neurons, APOE reduced the level of reelin-induced intracellular tyrosine phosphorylation of Dab1. The authors suggested that reelin directs neuronal migration by binding to VLDLR and APOER2. </p><p>Mutation of the Reln gene in the mouse disrupts neuronal migration in several brain regions and gives rise to functional deficits, such as ataxic gait and trembling. Thus, reelin is thought to control cell-cell interactions critical for cell positioning in the brain. Although an abundance of reelin transcript is found in the embryonic spinal cord, it was generally thought that neuronal migration in the spinal cord is not affected by reelin. However, Yip et al. (2000) showed that migration of sympathetic preganglionic neurons in the spinal cord is affected by reelin. This study indicated that reelin affects neuronal migration outside of the brain. Moreover, the relationship between reelin and migrating preganglionic neurons suggests that reelin acts as a barrier to neuronal migration. </p><p>Using neuronal precursors from postnatal mice in a Matrigel culture system, Hack et al. (2002) showed that reelin acted as a detachment signal for chain-migrating interneuron precursors in the olfactory bulb, inducing their dispersal into individual cells. In vivo studies of reeler mutant mice showed disrupted organization of the olfactory bulb as well as failure of individual neuronal migration. Reelin did not act as a stop signal, did not provide directional cues, and did not affect migration distance. </p><p>Using in vitro and in vivo migration assays, Dulabon et al. (2000) showed that reelin inhibits migration of cortical neurons in mouse embryonic brain. Immunoprecipitation experiments showed that reelin associates with alpha-3-beta-1 integrin (see 605025 and 135630), a receptor that mediates neuronal adhesion to radial glial fibers and radial migration. Using alpha-3-beta-1 integrin-deficient mouse embryos for migration assays, Dulabon et al. (2000) showed that deficiency in functional alpha-3-beta-1 integrins leads to deficiency in reelin function. They observed reduced levels of Dab1 protein and elevated expression of a 180-kD reelin fragment in cerebral cortices of alpha-3-beta-1 integrin-deficient mice. Dulabon et al. (2000) concluded that reelin may arrest neuronal migration and promote normal cortical lamination by binding alpha-3-beta-1 integrin and modulating integrin-mediated cellular adhesion. </p><p>By examining mice deficient in either Reln or Dab1, Rice et al. (2001) found that expression of both genes was essential for the patterning of synaptic connectivity in the retina. Physiologic studies of mice deficient in either gene detected attenuated rod-driven retinal responses that were associated with a decrease in rod bipolar cell density and an abnormal distribution of processes in the inner plexiform layer. </p><p>Grayson et al. (2005) found that postmortem brains from patients with schizophrenia had increased methylation of the RELN gene within the promoter region, particularly at positions -134 and -139, compared to controls. The authors hypothesized that hypermethylation of this promoter region results in decreased expression of RELN in schizophrenia. </p><p>Botella-Lopez et al. (2006) found increased levels of a 180-kD reelin fragment in CSF from 19 patients with Alzheimer disease (AD; 104300) compared to 11 nondemented controls. Western blot and PCR analysis confirmed increased levels of reelin protein and mRNA in tissue samples from the frontal cortex of AD patients. Reelin was not increased in plasma samples, suggesting distinct cellular origins. The reelin 180-kD fragment was also increased in CSF samples of other neurodegenerative disorders, including frontotemporal dementia (600274), progressive supranuclear palsy (PSP; 601104), and Parkinson disease (PD; 168600). </p><p>Using overexpression and knockdown studies with cultured rat and mouse hippocampal and cortical neurons, Matsuki et al. (2010) found that a signaling pathway containing Stk25 (602255), Lkb1 (STK11; 602216), Strad (STRADA; 608626), and the Golgi protein Gm130 (GOLGA2; 602580) promoted Golgi condensation and multiple axon outgrowth while inhibiting Golgi deployment into dendrites and dendritic growth. This signaling pathway acted in opposition to the reelin-Dab1 pathway, which tended to inhibit Golgi condensation and axon outgrowth and favor Golgi deployment into dendrites and dendrite outgrowth. </p><p>Thirty percent of all cortical interneurons arise from a relatively novel source within the ventral telencephalon, the caudal ganglionic eminence (CGE) (summary by De Marco Garcia et al., 2011). Owing to their late birth date, these interneurons populate the cortex only after the majority of other interneurons and pyramidal cells are already in place and have started to functionally integrate. De Marco Garcia et al. (2011) demonstrated in mice that for CGE-derived reelin-positive and calretinin (114051)-positive, but not vasoactive intestinal peptide (VIP; 192320)-positive, interneurons, activity is essential before postnatal day 3 for correct migration, and that after postnatal day 3, glutamate-mediated activity controls the development of their axons and dendrites. Furthermore, De Marco Garcia et al. (2011) showed that the engulfment and cell motility-1 gene (Elmo1; 606420), a target of the transcription factor distal-less homeobox-1 (Dlx1; 600029), is selectively expressed in reelin-positive and calretinin-positive interneurons and is both necessary and sufficient for activity-dependent interneuron migration. De Marco Garcia et al. (2011) concluded that their findings revealed a selective requirement for activity in shaping the cortical integration of specific neuronal subtypes. </p><p>Senturk et al. (2011) showed that the neuronal guidance cues ephrin B proteins are essential for Reelin signaling during the development of laminated structures in the brain. They showed that ephrin Bs genetically interact with Reelin. Notably, compound mouse mutants (Reln heterozygotes null for either Efnb2 (600527) or Efnb3 (602297)) and triple Efnb1 (300035)/Efnb2/Efnb3 knockouts showed neuronal migration defects that recapitulated the ones observed in the neocortex, hippocampus, and cerebellum of the reeler mouse. Mechanistically, Senturk et al. (2011) showed that Reelin binds to the extracellular domain of ephrin Bs, which associate at the membrane with VLDLR (192977) and ApoER2 (602600) in neurons. Clustering of ephrin Bs leads to the recruitment and phosphorylation of Dab1 (603448) which is necessary for Reelin signaling. Conversely, loss of function of ephrin Bs severely impairs Reelin-induced Dab1 phosphorylation. Importantly, activation of ephrin Bs can rescue the reeler neuronal migration defects in the absence of Reelin protein. Senturk et al. (2011) concluded that their results identified ephrin Bs as essential components of the Reelin receptor/signaling pathway to control neuronal migration during the development of the nervous system. </p><p>Shim et al. (2012) showed that SOX4 (184430) and SOX11 (600898) are crucial in regulating reelin expression and the inside-out pattern of cortical layer formation. This regulation is independent of E4, a conserved nonexonic element required for the specification of corticospinal neuron identity and connectivity, and Fezf2 (607414), and probably involves interactions with distinct regulatory elements. Cortex-specific double deletion of Sox4 and Sox11 in mice led to the loss of Fezf2 expression, failed specification of corticospinal neurons and, independent of Fezf2, a reeler-like inversion of layers. </p><p>In rat brain, Dazzo et al. (2015) found that Reln and Lgi1 (604619) colocalized in neurons in the temporal cortex and hippocampus, suggesting that they are involved in a common molecular pathway. </p><p>Segarra et al. (2018) found that the neuronal guidance cue reelin possesses proangiogenic activities that ensure the communication of endothelial cells with the glia to control neuronal migration and the establishment of the blood-brain barrier in the mouse brain. Apoer2 and Dab1 expressed in endothelial cells are required for vascularization of the retina and the cerebral cortex. Deletion of Dab1 in endothelial cells leads to a reduced secretion of laminin-alpha 4 (LAMA4; 600133) and decreased activation of integrin-beta 1 (ITGB1; 135630) in glial cells, which in turn control neuronal migration and barrier properties of the neurovascular unit. Thus, Segarra et al. (2018) concluded that reelin signaling in the endothelium is an instructive and integrative cue essential for neuro-glia-vascular communication. </p>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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<span class="mim-text-font">
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<p>Zaki et al. (2007) reported 2 sibs from a consanguineous Egyptian marriage who had cortical lissencephaly with cerebellar hypoplasia, severe epilepsy, and mental retardation. Karyotype analysis identified a homozygous, apparently balanced reciprocal translocation, t(7;12)(q22;p13), in both children. Further analysis confirmed disruption of the RELN gene at chromosome 7q22.1 and undetectable levels of the protein in both children. The unaffected parents were related as double first cousins were heterozygous for the translocation. </p>
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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><strong><em>Lissencephaly 2</em></strong></p><p>
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Normal development of the cerebral cortex requires long-range migration of cortical neurons from proliferative regions deep in the brain. Lissencephaly ('smooth brain,' from 'lissos,' meaning 'smooth,' and 'encephalos,' meaning 'brain') is a severe developmental disorder in which neuronal migration is impaired, leading to a thickened cerebral cortex whose normally folded contour is simplified and smooth. Hong et al. (2000) studied an autosomal recessive form of lissencephaly associated with severe abnormalities of the cerebellum, hippocampus, and brainstem (LIS2; 257320). They tested for linkage to markers near RELN on chromosome 7 and DAB1 on chromosome 1p32-p31 because mutations in the mouse homologs of these 2 genes cause brain defects in mice that resemble lissencephaly, including hypoplasia of the cerebellum, brainstem abnormalities, and a neuronal migration disorder of the neocortex and hippocampus. In 2 unrelated pedigrees, they found substantial regions of homozygosity in affected children near the RELN gene on chromosome 7q22. In these 2 families, they identified different splice site mutations in the RELN gene (600514.0001 and 600514.0002, respectively). The study of these patients pointed to several previously unsuspected functions of reelin in and outside of the brain. Although abnormalities of RELN mRNA had been reported in postmortem brains of humans with schizophrenia (Impagnatiello et al., 1998), no evidence of schizophrenia was found in individuals with heterozygous or homozygous RELN mutations. On the other hand, one of the lissencephaly patients studied with a muscle biopsy showed evidence of abnormal neuromuscular connectivity (Hourihane et al., 1993). Moreover, at least 3 patients had persistent lymphedema neonatally, and one showed accumulation of chylous (i.e., fatty) ascites fluid that required peritoneal shunting (Hourihane et al., 1993). The apparent role for reelin in serum homeostasis may reflect reelin interactions with LDL superfamily receptors outside the brain, as well as in the brain. </p><p>In a Moroccan girl (patient 1), born to consanguineous parents, with LIS2, Valence et al. (2016) identified a homozygous splice site mutation in the RELN gene (c.8844-2A-G; 600514.0007). Valence et al. (2016) noted that the severity of the patient's neocortical defect, involvement of the cerebellar hemispheres with absent folia, and level of disability were strongly suggestive of a defect in the reelin pathway. </p><p><strong><em>Familial Temporal Lobe Epilepsy 7</em></strong></p><p>
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In 7 unrelated families of Italian descent with familial temporal lobe epilepsy-7 (ETL7; 616436), Dazzo et al. (2015) identified 7 different heterozygous missense mutations in the RELN gene (see, e.g., 600514.0003-600514.0006). Mutations in the LGI1 gene (604619) had been excluded in these families. RELN mutations in the first 4 families were found by whole-exome sequencing; mutations in the 3 subsequent families were found by parallel sequencing of RELN exons in 11 small families with the disorder. Functional studies of the variants were not performed, but 3-dimensional modeling predicted that the mutations would result in structural defects and protein misfolding, which could lead to degradation of the altered proteins. Affected individuals from 4 families had reduced (up to 50%) serum levels of the main 310-kD reelin isoform compared to controls, which most likely resulted from impaired secretion of the altered proteins from hepatocytes. These findings suggested that the mutations resulted in a loss of function. Overall, RELN mutations occurred in 7 (17.5%) of 40 families studied; mutations were not found in families with mesial temporal lobe epilepsy, suggesting that RELN mutations may specifically cause lateral temporal lobe epilepsy. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between variation in the RELN gene and otosclerosis, see 166800.</p>
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<h4>
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<strong>Animal Model</strong>
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</h4>
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<span class="mim-text-font">
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<p>To investigate Reln function, Magdaleno et al. (2002) generated transgenic mice using the nestin (NES; 600915) promoter to drive ectopic expression of Reln in the ventricular zone during early brain development. Ectopic Reln expression in transgenic reelin mice, which lack endogenous Reln expression, induced tyrosine phosphorylation of Dab1 in the ventricular zone. The transgene also rescued some, but not all, of the neuroanatomic and behavioral abnormalities characteristic of the reeler phenotype, including ataxia and the migration of Purkinje cells. Magdaleno et al. (2002) hypothesized that Reln functions in concert with other positional cues to promote cell-cell interactions that are required for layer formation during development. </p><p>Assadi et al. (2003) investigated interactions between the reelin signaling pathway and Lis1 in brain development. Compound mutant mice with disruptions in the Reln pathway and heterozygous mutations in the Pafah1b1 gene, which encodes Lis1, had a higher incidence of hydrocephalus and enhanced cortical and hippocampal layering defects. The Dab1 signaling molecule and Lis1 bound in a reelin-induced phosphorylation-dependent manner. These data indicated genetic and biochemical interaction between the reelin signaling pathway and LIS1. </p><p>In the mouse ventral spinal cord, Hochstim et al. (2008) identified 3 subtypes of white matter astrocytes with differential gene expression corresponding to position. Astrocytes expressing both Reln and Slit1 (603742) were in the ventrolateral domain, those expressing Reln only were at the dorsolateral domain, and those expressing Slit1 only were at the ventromedial domain. The distinct positions of these astrocytes were specified by varying expression of the homeodomain transcription factors Pax6 (607108) and Nkx6.1 (602563). The findings indicated that positional identity is an organizing principle underlying phenotypic diversity among white matter astrocytes, as well as among neurons, and that this diversity is prespecified within precursor cells in the germinal zone of the CNS. </p><p>Miller and Sweatt (2007) found that DNA methylation, which is mediated by DNA methyltransferase, was dynamically regulated during learning and memory consolidation in adult rats. Animals exposed to an associative context plus shock showed increased Dnmt3a (602769) and Dnmt3b (602900) mRNA in hippocampal area CA1 compared to context-only animals. Context plus shock rats showed increased methylation and decreased mRNA of the memory suppressor gene PP1C-beta (PPP1CB; 600590) compared to shock-only controls, as well as increased demethylation and increased mRNA levels of reelin, which is involved in synaptic plasticity, compared to controls. The methylation levels of both these target genes returned to baseline within a day, indicating rapid and dynamic changes. Treatment with a DNMT inhibitor blocked the methylation changes and prevented memory consolidation of fear-conditioned learning, but the memory changes were plastic, and memory consolidation was reestablished after the inhibitor wore off. Miller and Sweatt (2007) noted that DNA methylation has been viewed as having an exclusive role in development, but they emphasized that their findings indicated that rapid and dynamic alteration of DNA methylation can occur in the adult central nervous system in response to environmental stimuli during associative learning in the hippocampus. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Quattrocchi et al. (2003) concluded that mouse reelin functions postnatally to regulate the development of the neuromuscular junction. Because these results could not be replicated, Quattrocchi et al. (2004) retracted their paper from Science of 2003. The results had been called into question by Bidoia et al. (2004) and others. D'Arcangelo (2004) could not reproduce the findings described by Quattrocchi et al. (2003) and concluded that reelin does not regulate the development of the neuromuscular junction. </p>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>7 Selected Examples):</strong>
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</span>
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</h4>
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<p />
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<h4>
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<span class="mim-font">
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<strong>.0001 LISSENCEPHALY 2</strong>
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</span>
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</h4>
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<div>
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<span class="mim-text-font">
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RELN, IVS37AS, G-A, -1
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<br />
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SNP: rs2117170464,
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ClinVar: RCV000009652
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<span class="mim-text-font">
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<p>In 3 children, born of consanguineous Saudi Arabian parents, with lissencephaly-2 (LIS2; 257320), Hong et al. (2000) identified a homozygous splice acceptor site mutation in the RELN gene: IVS37AS, G-A, -1. The parents were heterozygous for the mutation. In their article, Hong et al. (2000) referred to this mutation as IVS36AS, G-A, -1; however, in an erratum, they noted that their system for exon numbering differed from that adopted in the mouse and clarified the human-mouse comparison so that a single numbering system could be used in both species. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 LISSENCEPHALY 2</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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RELN, 148-BP DEL
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ClinVar: RCV000009653
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<span class="mim-text-font">
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<p>In a British family in which the parents were related as half first cousins, Hong et al. (2000) identified a homozygous 148-bp deletion in the RELN gene, corresponding to the removal of exon 42 (EX42DEL), in 3 brothers, including a set of identical twins, with lissencephaly-2 (LIS2; 257320). The family had previously been reported by Hourihane et al. (1993). At birth, the children showed normal head size, congenital lymphedema, and hypotonia. Brain MRI showed moderate lissencephaly and profound cerebellar hypoplasia. Cognitive development was delayed for all affected children, with little or no language and no ability to sit or stand unsupported. There was also myopia, nystagmus, and generalized seizures that could be controlled with medication. In 1 brother, muscle biopsy showed evidence of abnormal neuromuscular connectivity. One brother showed accumulation of chylous (that is, fatty) ascites fluid that required peritoneal shunting. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>.0003 EPILEPSY, FAMILIAL TEMPORAL LOBE, 7</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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RELN, HIS798ASN
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<br />
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SNP: rs794727996,
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ClinVar: RCV000180785
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<div>
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<span class="mim-text-font">
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<p>In an Italian family (F31) with familial temporal lobe epilepsy-7 (ETL7; 616436), Dazzo et al. (2015) identified a heterozygous c.2392C-A transversion (c.2392C-A, NM_005045.3) in the RELN gene, resulting in a his798-to-asn (H798N) substitution at a highly conserved residue in the Asp-box-2 domain. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project or Exome Variant Server databases, or in 270 controls. A 3-dimensional structural model predicted that the mutation would have a deleterious effect on the organization of reelin repeats. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 EPILEPSY, FAMILIAL TEMPORAL LOBE, 7</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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RELN, GLY2783CYS
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<br />
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SNP: rs794727997,
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gnomAD: rs794727997,
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ClinVar: RCV000180786
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an Italian family (F14) with familial temporal lobe epilepsy-7 (ETL7; 616436), Dazzo et al. (2015) identified a heterozygous c.8347G-T transversion (c.8347G-T, NM_005045.3) in the RELN gene, resulting in a gly2783-to-cys (G2783C) substitution at a highly conserved residue in the Asp-box-13 domain. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project or Exome Variant Server databases, or in 270 controls. A 3-dimensional structural model predicted that the mutation would have a deleterious effect on the organization of reelin repeats. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 EPILEPSY, FAMILIAL TEMPORAL LOBE, 7</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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RELN, ASP763GLY
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<br />
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SNP: rs794727998,
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ClinVar: RCV000180787
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 members of a family (FIA) with familial temporal lobe epilepsy-7 (ETL7; 616436), Dazzo et al. (2015) identified a heterozygous c.2288A-G transition (c.2288A-G, NM_005045.3) in the RELN gene, resulting in an asp763-to-gly (D763G) substitution at a highly conserved residue in repeat 1. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project or Exome Variant Server databases, or in 270 controls. A 3-dimensional structural model predicted that the mutation would perturb the horseshoe-like arrangement of repeat 1. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 EPILEPSY, FAMILIAL TEMPORAL LOBE, 7</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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RELN, GLU3176LYS
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<br />
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SNP: rs794727999,
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ClinVar: RCV000180788
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sisters (family PAC) with familial temporal lobe epilepsy-7 (ETL7; 616436), Dazzo et al. (2015) identified a heterozygous c.9526G-A transition (c.9526G-A, NM_005045.3) in the RELN gene, resulting in a glu3176-to-lys (E3176K) substitution at a highly conserved residue in repeat 8. The mutation, which was found by direct sequencing of RELN exons in 11 families with the disorder, was not found in the 1000 Genomes Project or Exome Variant Server databases, or in 270 controls. A 3-dimensional structural model predicted that the mutation would disrupt a structurally important interaction. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0007 LISSENCEPHALY 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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RELN, c.8842-2A-G
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<br />
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ClinVar: RCV003325325
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a Moroccan girl (patient 1), born to consanguineous parents, with lissencephaly-2 (LIS2; 257320), Valence et al. (2016) identified homozygosity for a c.8844-2A-G transition in the RELN gene, predicted to result in abnormal splicing and skipping of exon 54, leading to premature termination of translation. The mutation was identified by sequencing of the RELN gene. The parents were not tested for the mutation. Functional studies were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Assadi, A. H., Zhang, G., Beffert, U., McNeil, R. S., Renfro, A. L., Niu, S., Quattrocchi, C. C., Antalffy, B. A., Sheldon, M., Armstrong, D. D., Wynshaw-Boris, A., Herz, J., D'Arcangelo, G., Clark, G. D.
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|
<strong>Interaction of reelin signaling and Lis1 in brain development.</strong>
|
|
Nature Genet. 35: 270-276, 2003.
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[PubMed: 14578885]
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[Full Text: https://doi.org/10.1038/ng1257]
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<p class="mim-text-font">
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Bidoia, C., Misgeld, T., Weinzierl, E., Buffelli, M., Feng, G., Cangiano, A., Lichtman, J. W., Sanes, J. R.
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|
<strong>Comment on 'reelin promotes peripheral synapse elimination and maturation.'</strong>
|
|
Science 303: 1977b, 2004.
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[PubMed: 15044788]
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[Full Text: https://doi.org/10.1126/science.1094146]
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<p class="mim-text-font">
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Botella-Lopez, A., Burgaya, F., Gavin, R., Garcia-Ayllon, M. S., Gomez-Tortosa, E., Pena-Casanova, J., Urena, J. M., Del Rio, J. A., Blesa, R., Soriano, E., Saez-Valero, J.
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<strong>Reelin expression and glycosylation patterns are altered in Alzheimer's disease.</strong>
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D'Arcangelo, G., Homayouni, R., Keshvara, L., Rice, D. S., Sheldon, M., Curran, T.
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<strong>Reelin is a ligand for lipoprotein receptors.</strong>
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Neuron 24: 471-479, 1999.
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[PubMed: 10571240]
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D'Arcangelo, G., Miao, G. G., Chen, S.-C., Soares, H. D., Morgan, J. I., Curran, T.
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<strong>A protein related to extracellular matrix proteins deleted in the mouse mutant reeler.</strong>
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[Full Text: https://doi.org/10.1038/374719a0]
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<p class="mim-text-font">
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D'Arcangelo, G.
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<strong>Personal Communication.</strong>
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|
Nutley, N. J. 6/2/1995.
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</p>
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<p class="mim-text-font">
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D'Arcangelo, G.
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<strong>Response to comment on 'reelin promotes peripheral synapse elimination and maturation.'</strong>
|
|
Science 303: 1977c only, 2004.
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</p>
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<p class="mim-text-font">
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Dazzo, E., Fanciulli, M., Serioli, E., Minervini, G., Pulitano, P., Binelli, S., Di Bonaventura, C., Luisi, C., Pasini, E., Striano, S., Striano, P., Coppola, G., and 11 others.
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<strong>Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy.</strong>
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Am. J. Hum. Genet. 96: 992-1000, 2015.
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[PubMed: 26046367]
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<p class="mim-text-font">
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De Marco Garcia, N. V., Karayannis, T., Fishell, G.
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<strong>Neuronal activity is required for the development of specific cortical interneuron subtypes.</strong>
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Nature 472: 351-355, 2011.
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[PubMed: 21460837]
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[Full Text: https://doi.org/10.1038/nature09865]
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<p class="mim-text-font">
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|
DeSilva, U., D'Arcangelo, G., Braden, V. V., Chen, J., Miao, G. G., Curran, T., Green, E. D.
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<strong>The human reelin gene: isolation, sequencing, and mapping on chromosome 7.</strong>
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Genome Res. 7: 157-164, 1997.
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[PubMed: 9049633]
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</p>
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<li>
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<p class="mim-text-font">
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Dulabon, L., Olson, E. C., Taglienti, M. G., Eisenhuth, S., McGrath, B., Walsh, C. A., Kreidberg, J. A., Anton, E. S.
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<strong>Reelin binds alpha-3-beta-1 integrin and inhibits neuronal migration.</strong>
|
|
Neuron 27: 33-44, 2000.
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|
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[PubMed: 10939329]
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[Full Text: https://doi.org/10.1016/s0896-6273(00)00007-6]
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</p>
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<li>
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<p class="mim-text-font">
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Grayson, D. R., Jia, X., Chen, Y., Sharma, R. P., Mitchell, C. P., Guidotti, A., Costa, E.
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<strong>Reelin promoter hypermethylation in schizophrenia.</strong>
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Proc. Nat. Acad. Sci. 102: 9341-9346, 2005.
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[PubMed: 15961543]
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<p class="mim-text-font">
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Green, M. C.
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<strong>Catalog of mutant genes and polymorphic loci.In: Lyon, M. F.; Searle, A. G. (eds.) : Genetic Variants and Strains of the Laboratory Mouse. (2nd ed.)</strong>
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Oxford: Oxford Univ. Press (pub.) 1989.
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<p class="mim-text-font">
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Hack, I., Bancila, M., Loulier, K., Carroll, P., Cremer, H.
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<strong>Reelin is a detachment signal in tangential chain-migration during postnatal neurogenesis.</strong>
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Nature Neurosci. 5: 939-945, 2002.
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[PubMed: 12244323]
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<p class="mim-text-font">
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Hiesberger, T., Trommsdorff, M., Howell, B. W., Goffinet, A., Mumby, M. C., Cooper, J. A., Herz, J.
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<strong>Direct binding of reelin to VLDL receptor and apoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation.</strong>
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Neuron 24: 481-489, 1999.
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<p class="mim-text-font">
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Hirotsune, S., Takahara, T., Sasaki, N., Hirose, K., Yoshiki, A., Ohashi, T., Kusakabe, M., Murakami, Y., Muramatsu, M., Watanabe, S., Nakao, K., Katsuki, M., Hayashizaki, Y.
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<strong>The reeler gene encodes a protein with an EGF-like motif expressed by pioneer neurons.</strong>
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Nature Genet. 10: 77-83, 1995.
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<p class="mim-text-font">
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Hochstim, C., Deneen, B., Lukaszewicz, A., Zhou, Q., Anderson, D. J.
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<strong>Identification of positionally distinct astrocyte subtypes whose identities are specified by a homeodomain code.</strong>
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<p class="mim-text-font">
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Hong, S. E., Shugart, Y. Y., Huang, D. T., Al Shahwan, S., Grant, P. E., Hourihane, J. O., Martin, N. D. T., Walsh, C. A.
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<strong>Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.</strong>
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Nature Genet. 26: 93-96, 2000. Note: Erratum: Nature Genet. 27: 225 only, 2001.
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<p class="mim-text-font">
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Hourihane, J. O., Bennett, C. P., Chaudhuri, R., Robb, S. A., Martin, N. D. T.
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<p class="mim-text-font">
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Impagnatiello, F., Guidotti, A. R., Pesold, C., Dwivedi, Y., Caruncho, H., Pisu, M. G., Uzunov, D. P., Smalheiser, N. R., Davis, J. M., Pandey, G. N., Pappas, G. D., Tueting, P., Sharma, R. P., Costa, E.
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<strong>A decrease of reelin expression as a putative vulnerability factor in schizophrenia.</strong>
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<p class="mim-text-font">
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Magdaleno, S., Keshvara, L., Curran, T.
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<strong>Rescue of ataxia and preplate splitting by ectopic expression of reelin in reeler mice.</strong>
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Neuron 33: 573-586, 2002.
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[PubMed: 11856531]
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[Full Text: https://doi.org/10.1016/s0896-6273(02)00582-2]
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<p class="mim-text-font">
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Matsuki, T., Matthews, R. T., Cooper, J. A., van der Brug, M. P., Cookson, M. R., Hardy, J. A., Olson, E. C., Howell, B. W.
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<strong>Reelin and Stk25 have opposing roles in neuronal polarization and dendritic Golgi deployment.</strong>
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Cell 143: 826-836, 2010.
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[PubMed: 21111240]
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[Full Text: https://doi.org/10.1016/j.cell.2010.10.029]
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<p class="mim-text-font">
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Miller, C. A., Sweatt, J. D.
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<strong>Covalent modification of DNA regulates memory formation.</strong>
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Neuron 53: 857-869, 2007. Note: Erratum: Neuron 59: 1051 only, 2008.
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[PubMed: 17359920]
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[Full Text: https://doi.org/10.1016/j.neuron.2007.02.022]
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</p>
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<li>
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<p class="mim-text-font">
|
|
Quattrocchi, C. C., Huang, C., Niu, S., Sheldon, M., Benhayon, D., Cartwright, J., Jr., Mosier, D. R., Keller, F., D'Arcangelo, G.
|
|
<strong>Reelin promotes peripheral synapse elimination and maturation.</strong>
|
|
Science 301: 649-653, 2003. Note: Erratum: Science 301: 1849 only, 2003. Retraction: Science 303: 1974 only, 2004.
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|
[PubMed: 12893944]
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[Full Text: https://doi.org/10.1126/science.1082690]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Quattrocchi, C. C., Huang, C., Niu, S., Sheldon, M., Benhayon, D., Cartwright, J., Jr., Mosier, D. R., Keller, F., D'Arcangelo, G.
|
|
<strong>Retraction. (Letter)</strong>
|
|
Science 303: 1974 only, 2004.
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|
|
[PubMed: 15044784]
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Hilary J. Vernon - updated : 08/30/2023<br>Ada Hamosh - updated : 11/20/2018<br>Cassandra L. Kniffin - updated : 6/24/2015<br>Ada Hamosh - updated : 7/17/2012<br>Ada Hamosh - updated : 7/8/2011<br>Patricia A. Hartz - updated : 2/10/2011<br>Marla J. F. O'Neill - updated : 4/13/2009<br>Cassandra L. Kniffin - updated : 5/15/2008<br>Cassandra L. Kniffin - updated : 7/18/2007<br>Cassandra L. Kniffin - updated : 5/24/2006<br>Patricia A. Hartz - updated : 12/7/2005<br>Cassandra L. Kniffin - updated : 7/11/2005<br>Ada Hamosh - updated : 4/7/2004<br>Victor A. McKusick - updated : 10/31/2003<br>Ada Hamosh - updated : 8/12/2003<br>Dawn Watkins-Chow - updated : 10/31/2002<br>Cassandra L. Kniffin - updated : 9/16/2002<br>Dawn Watkins-Chow - updated : 6/13/2002<br>Dawn Watkins-Chow - updated : 11/25/2001<br>Victor A. McKusick - updated : 9/27/2000<br>Victor A. McKusick - updated : 8/29/2000<br>Wilson H. Y. Lo - updated : 4/6/2000<br>Stylianos E. Antonarakis - updated : 7/8/1999<br>Victor A. McKusick - updated : 3/1/1999<br>Victor A. McKusick - updated : 4/8/1997
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