3154 lines
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Entry
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- *603448 - DAB ADAPTOR PROTEIN 1; DAB1
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- OMIM
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<p>
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<span class="h4">*603448</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/603448">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<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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<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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<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 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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<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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<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=ENSG00000173406;t=ENST00000371236" 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=1600" 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=603448" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<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=ENSG00000173406;t=ENST00000371236" 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_001353980,NM_001353983,NM_001353985,NM_001353986,NM_001365792,NM_001365793,NM_001365794,NM_001365795,NM_001379461,NM_001379462,NM_021080" 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_001365792" 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=603448" 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=04582&isoform_id=04582_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/DAB1" 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/3288852,21954748,33350928,45767671,45768290,45768837,119627042,119627043,133777332,150421536,193787872,929654730,1227367055,1227367082,1237938270,1237938288,1475409272,1475409274,1475409301,1475409322,1523730279,1828054680,1828054790" 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/O75553" 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=1600" 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=ENSG00000173406;t=ENST00000371236" 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=DAB1" 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=DAB1" 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+1600" 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/DAB1" 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:1600" 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/1600" 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=chr1&hgg_gene=ENST00000371236.7&hgg_start=56994778&hgg_end=58546726&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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603448[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=603448[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/DAB1/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/ENSG00000173406" 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=DAB1" 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=DAB1" 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=DAB1" 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=DAB1&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/PA27131" 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:2661" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0000414.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:108554" 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/DAB1#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:108554" 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/1600/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=1600" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00000894;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-060421-7958" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:1600" 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=DAB1&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> 719301002<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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603448
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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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DAB ADAPTOR PROTEIN 1; DAB1
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
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<div>
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<h4>
|
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<span class="mim-font">
|
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DISABLED, DROSOPHILA, HOMOLOG OF, 1
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=DAB1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">DAB1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/1/653?start=-3&limit=10&highlight=653">1p32.2-p32.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:56994778-58546726&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'})">1:56,994,778-58,546,726</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
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Location
|
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
|
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</th>
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
|
<a href="/geneMap/1/653?start=-3&limit=10&highlight=653">
|
|
1p32.2-p32.1
|
|
</a>
|
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</span>
|
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</td>
|
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|
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<td>
|
|
<span class="mim-font">
|
|
Spinocerebellar ataxia 37
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/615945"> 615945 </a>
|
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|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/603448" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/603448" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
|
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<p />
|
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</div>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="text" class="mim-anchor"></a>
|
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<h4>
|
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|
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<span class="mim-font">
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<p>The reelin (RELN; <a href="/entry/600514">600514</a>) signaling pathway plays a critical role in the correct positioning of neurons within the developing brain. Animal studies have shown that DAB1 serves as an intracellular adaptor that is tyrosine phosphorylated when reelin binds to the lipoprotein receptors VLDLR (<a href="/entry/192977">192977</a>) and APOER2 (LRP8; <a href="/entry/602600">602600</a>) on the surface of neurons (<a href="#7" class="mim-tip-reference" title="Huang, Y., Shah, V., Liu, T., Keshvara, L. <strong>Signaling through Disabled 1 requires phosphoinositide binding.</strong> Biochem. Biophys. Res. Commun. 331: 1460-1468, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15883038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15883038</a>] [<a href="https://doi.org/10.1016/j.bbrc.2005.04.064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15883038">Huang et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15883038" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By RT-PCR of human embryonic brain RNA using degenerate primers based on mouse Dab1, <a href="#8" class="mim-tip-reference" title="Lambert de Rouvroit, C., Goffinet, A. M. <strong>Cloning of human DAB1 and mapping to chromosome 1p31-p32.</strong> Genomics 53: 246-247, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9790777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9790777</a>] [<a href="https://doi.org/10.1006/geno.1998.5523" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9790777">Lambert de Rouvroit and Goffinet (1998)</a> cloned human DAB1. The deduced 555-amino acid protein contains a putative N-terminal phosphotyrosine-binding (PTB) domain. DAB1 shares 96% overall amino acid identity with the 555-amino acid mouse Dab1 isoform, and the 2 proteins are identical over their first 271 amino acids. DAB1 shares significant similarity with Drosophila 'disabled' (dab). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9790777" 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 5-prime RACE of human and mouse embryonic brain RNA, <a href="#1" class="mim-tip-reference" title="Bar, I., Tissir, F., Lambert de Rouvroit, C., De Backer, O., Goffinet, A. M. <strong>The gene encoding Disabled-1 (DAB1), the intracellular adaptor of the reelin pathway, reveals unusual complexity in human and mouse.</strong> J. Biol. Chem. 278: 5802-5812, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12446734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12446734</a>] [<a href="https://doi.org/10.1074/jbc.M207178200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12446734">Bar et al. (2003)</a> identified 6 alternative 5-prime UTRs for human DAB1 and 4 alternative 5-prime UTRs for mouse Dab1. Three 5-prime UTRs, which the authors called UTRs 1A, 1B, and 1D, are conserved between mouse and human. UTR 1B, which contains 7 exons in human and 10 exons in mouse, contains several upstream ORFs and numerous upstream ATG codons preceding the major translation initiation site, and some of the ORFs are conserved between mouse and human. RT-PCR of mouse tissues detected transcripts containing UTR 1B only in brain, whereas transcripts containing UTRs 1A and 1D were detected in brain, testis, kidney, and liver, but not in spleen, heart, or thymus. PCR analysis of mouse brain at various developmental stages revealed weak UTR 1B expression at embryonic days 11 and 12, and stronger expression at embryonic day 15, at birth, and in adult. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12446734" 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 RT-PCR, <a href="#10" class="mim-tip-reference" title="McAvoy, S., Zhu, Y., Perez, D. S., James, C. D., Smith, D. I. <strong>Disabled-1 is a large common fragile site gene, inactivated in multiple cancers.</strong> Genes Chromosomes Cancer 47: 165-174, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18008369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18008369</a>] [<a href="https://doi.org/10.1002/gcc.20519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18008369">McAvoy et al. (2008)</a> found that DAB1 was expressed in all normal human tissues examined, including brain, breast, cervix, endometrium, prostate, and ovary. It was also expressed in cell lines derived from normal ovarian surface epithelium and normal breast epithelium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18008369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Seixas, A. I., Loureiro, J. R., Costa, C., Ordonez-Ugalde, A., Marcelino, H., Oliveira,, C. L., Loureiro, J. L., Dhingra, A., Brandao, E., Cruz, V. T., Timoteo, A., Quintans, B., and 9 others. <strong>A pentanucleotide ATTTC repeat insertion in the non-coding region of DAB1, mapping to SCA37, causes spinocerebellar ataxia.</strong> Am. J. Hum. Genet. 101: 87-103, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28686858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28686858</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28686858[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.2017.06.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28686858">Seixas et al. (2017)</a> noted that the expression of DAB1 is very complex because it contains several alternative first exons that can result in transcripts with variable 5-prime UTRs. Various transcripts were found in multiple human central nervous system regions, including the cerebellum, and all showed higher expression in human fetal brain tissue compared to adult brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28686858" 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="#1" class="mim-tip-reference" title="Bar, I., Tissir, F., Lambert de Rouvroit, C., De Backer, O., Goffinet, A. M. <strong>The gene encoding Disabled-1 (DAB1), the intracellular adaptor of the reelin pathway, reveals unusual complexity in human and mouse.</strong> J. Biol. Chem. 278: 5802-5812, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12446734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12446734</a>] [<a href="https://doi.org/10.1074/jbc.M207178200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12446734">Bar et al. (2003)</a> determined that the DAB1 gene spans more than 1.2 Mb. Exons 2 through 14 span more than 294 kb and contain the coding region for the major DAB1 isoform. Exon 15 contains the 3-prime UTR. Multiple 5-prime exons are spread over a 961-kb region and produce 6 alternative 5-prime UTRs. The most complex 5-prime UTR, UTR 1B, is made up of 7 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12446734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By analysis of radiation hybrids, <a href="#8" class="mim-tip-reference" title="Lambert de Rouvroit, C., Goffinet, A. M. <strong>Cloning of human DAB1 and mapping to chromosome 1p31-p32.</strong> Genomics 53: 246-247, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9790777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9790777</a>] [<a href="https://doi.org/10.1006/geno.1998.5523" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9790777">Lambert de Rouvroit and Goffinet (1998)</a> mapped the DAB1 gene to chromosome 1p32-p31. This region shows homology of synteny with the segment of mouse chromosome 4 containing Dab1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9790777" 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>Studies in mice have shown that layering of neurons in the cerebral cortex and cerebellum requires Reln and Dab1 (see ANIMAL MODEL). By targeted disruption experiments in mice, <a href="#17" 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, Vldlr and Apoer2, 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="#4" 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 bound directly and specifically to the extracellular domains of Vldlr and ApoER2. Blockade of Vldlr and ApoER2 ligand binding correlated with loss of Reelin-induced Dab1 tyrosine phosphorylation. With Western blot analysis, they demonstrated that mice lacking either Reln or Vldlr and ApoER2 (<a href="#17" 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>) exhibited a dramatic increase in the phosphorylation level of the microtubule-stabilizing protein tau (MAPT; <a href="/entry/157140">157140</a>). <a href="#4" 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=10571241+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 immunolabeling, <a href="#3" 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> detected coexpression of Dab1 and alpha-3 (ITGA3; <a href="/entry/605025">605025</a>)-beta-1 (ITGB1; <a href="/entry/135630">135630</a>) integrin receptor in mouse embryonic cortical neurons with overlapping subcellular localization. They also observed reduced levels of Dab1 protein and elevated expression of a Reln fragment in cerebral cortices of alpha-3-beta-1 integrin-deficient mice. <a href="#3" 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/alpha-3-beta-1 integrin interactions regulate Dab1 protein levels but not Dab1 phosphorylation. <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><a href="#7" class="mim-tip-reference" title="Huang, Y., Shah, V., Liu, T., Keshvara, L. <strong>Signaling through Disabled 1 requires phosphoinositide binding.</strong> Biochem. Biophys. Res. Commun. 331: 1460-1468, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15883038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15883038</a>] [<a href="https://doi.org/10.1016/j.bbrc.2005.04.064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15883038">Huang et al. (2005)</a> stated that the PTB domain of mouse Dab1 binds to APP (<a href="/entry/104760">104760</a>)-type transmembrane receptors and to lipoprotein receptors. The PTB domain also exhibits a pleckstrin (PLEK; <a href="/entry/173570">173570</a>) homology (PH) domain-like function, whereby it binds to phosphoinositides (PI), with lys45 being critical for binding to phosphatidylinositol-4,5-bisphosphate. <a href="#7" class="mim-tip-reference" title="Huang, Y., Shah, V., Liu, T., Keshvara, L. <strong>Signaling through Disabled 1 requires phosphoinositide binding.</strong> Biochem. Biophys. Res. Commun. 331: 1460-1468, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15883038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15883038</a>] [<a href="https://doi.org/10.1016/j.bbrc.2005.04.064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15883038">Huang et al. (2005)</a> found that PI binding targeted Dab1 to the membrane, where it was subject to basal phosphorylation independent of reelin, Vldlr, and Apoer2. This receptor-independent membrane targeting of Dab1 was required for interaction of Dab1 with the downstream signaling proteins Src (<a href="/entry/190090">190090</a>) and Crk (<a href="/entry/164762">164762</a>), and disruption of PI binding prevented reelin-induced Dab1 hyperphosphorylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15883038" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Honda, T., Nakajima, K. <strong>Mouse Disabled 1 (DAB1) is a nucleocytoplasmic shuttling protein.</strong> J. Biol. Chem. 281: 38951-38965, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17062576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17062576</a>] [<a href="https://doi.org/10.1074/jbc.M609061200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17062576">Honda and Nakajima (2006)</a> found that mouse Dab1 shuttled between the cytoplasm and nucleus. Inhibition of the Ran (<a href="/entry/601179">601179</a>)-GTP-dependent nuclear export protein Crm1 (XPO1; <a href="/entry/602559">602559</a>) in a mouse neuroblastoma cell line resulted in nuclear accumulation of Dab1. Mutagenesis analysis revealed that Dab1 contains 2 leucine-rich nuclear export signal sequences and a bipartite nuclear localization signal sequence. <a href="#5" class="mim-tip-reference" title="Honda, T., Nakajima, K. <strong>Mouse Disabled 1 (DAB1) is a nucleocytoplasmic shuttling protein.</strong> J. Biol. Chem. 281: 38951-38965, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17062576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17062576</a>] [<a href="https://doi.org/10.1074/jbc.M609061200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17062576">Honda and Nakajima (2006)</a> also showed that Dab1 interacted directly with Crm1 in a Ran-GTP-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17062576" 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="McAvoy, S., Zhu, Y., Perez, D. S., James, C. D., Smith, D. I. <strong>Disabled-1 is a large common fragile site gene, inactivated in multiple cancers.</strong> Genes Chromosomes Cancer 47: 165-174, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18008369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18008369</a>] [<a href="https://doi.org/10.1002/gcc.20519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18008369">McAvoy et al. (2008)</a> found that DAB1 mRNA and protein expression was reduced in a variety of human cancers, especially in brain and endometrial cancers. Experimental overexpression of DAB1 in a human breast cancer cell line inhibited cell growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18008369" 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="#9" 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><a href="#13" 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 (<a href="/entry/600514">600514</a>) 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. APOE receptor 2 (<a href="/entry/602600">602600</a>) 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="#13" 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>In 35 affected individuals from 3 large, multigenerational kindreds (pedigrees M, G, and R) from southern Portugal with spinocerebellar ataxia-37 (SCA37; <a href="/entry/615945">615945</a>), <a href="#14" class="mim-tip-reference" title="Seixas, A. I., Loureiro, J. R., Costa, C., Ordonez-Ugalde, A., Marcelino, H., Oliveira,, C. L., Loureiro, J. L., Dhingra, A., Brandao, E., Cruz, V. T., Timoteo, A., Quintans, B., and 9 others. <strong>A pentanucleotide ATTTC repeat insertion in the non-coding region of DAB1, mapping to SCA37, causes spinocerebellar ataxia.</strong> Am. J. Hum. Genet. 101: 87-103, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28686858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28686858</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28686858[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.2017.06.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28686858">Seixas et al. (2017)</a> identified a heterozygous 5-bp ATTTC(n) insertion in the 5-prime UTR intron 3 of the DAB1 gene. The insertion mutation, which was found by a complex process of linkage analysis, next-generation sequencing, PCR analysis, Southern blot analysis, and Sanger sequencing, segregated with the disorder in the families. Six affected individuals from 3 additional Portuguese families with SCA37 also carried the pathogenic insertion. Haplotype analysis was consistent with a founder effect in all 6 families. In vitro cellular expression studies showed that the ATTTC(n) insertion resulted in the formation of abnormal RNA aggregates with a nuclear localization. Injection of RNA containing the pathologic DAB1 repeat insertion into zebrafish embryos resulted in developmental defects and increased lethality. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28686858" 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 affected members of 4 unrelated families with SCA37, all from the same region in southern Spain, <a href="#2" class="mim-tip-reference" title="Corral-Juan, M., Serrano-Munuera, C., Rabano, A., Cota-Gonzalez, D., Segarra-Roca, A., Ispierto, L., Cano-Orgaz, A. T., Adarmes, A. D., Mendez-del-Barrio, C., Jesus, S., Mir, P., Volpini, V., Alvarez-Ramo, R., Sanchez, I., Matilla-Duenas, A. <strong>Clinical, genetic and neuropathological characterization of spinocerebellar ataxia type 37.</strong> Brain 141: 1981-1997, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29939198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29939198</a>] [<a href="https://doi.org/10.1093/brain/awy137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29939198">Corral-Juan et al. (2018)</a> identified an unstable intronic ATTTC(n) pentanucleotide repeat within a noncoding regulatory region of the DAB1 gene. The ATTTC repeat ranged from 46 to 71 repeats, and there was a significant inverse correlation between repeat size and age at onset in males, but not in females. Neuropathologic analysis of 2 patients showed that DAB1 was overexpressed in the cerebellum compared to controls, and DAB1 showed abnormal perisomatic and perinuclear punctate staining in remaining Purkinje cells. There was also dysregulated expression of DAB1 transcripts, reelin proteins, and upregulation of the reelin-DAB1 signaling pathway, which may adversely affect neuronal migration. <a href="#2" class="mim-tip-reference" title="Corral-Juan, M., Serrano-Munuera, C., Rabano, A., Cota-Gonzalez, D., Segarra-Roca, A., Ispierto, L., Cano-Orgaz, A. T., Adarmes, A. D., Mendez-del-Barrio, C., Jesus, S., Mir, P., Volpini, V., Alvarez-Ramo, R., Sanchez, I., Matilla-Duenas, A. <strong>Clinical, genetic and neuropathological characterization of spinocerebellar ataxia type 37.</strong> Brain 141: 1981-1997, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29939198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29939198</a>] [<a href="https://doi.org/10.1093/brain/awy137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29939198">Corral-Juan et al. (2018)</a> suggested that the mutation resulted in a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29939198" 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>Cortical neurons form in specialized proliferative regions deep in the brain and migrate past previously formed neurons to reach their proper layer. The laminar organization of multiple neuronal types in the cerebral cortex is required for normal cognitive function. The mouse 'reeler' mutation causes abnormal patterns of cortical neuronal migration and defects in cerebellar development and neuronal positioning in other brain regions. Reelin (RELN; <a href="/entry/600514">600514</a>), the product of the gene mutant in reeler, is an extracellular protein secreted by pioneer neurons. The mouse 'scrambler' and 'yotari' recessive mutations exhibit a phenotype identical to that of reeler. <a href="#18" class="mim-tip-reference" title="Ware, M. L., Fox, J. W., Gonzalez, J. L., Davis, N. M., Lambert de Rouvroit, C., Russo, C. J., Chua, S. C., Jr., Goffinet, A. M., Walsh, C. A. <strong>Aberrant splicing of a mouse disabled homolog, mdab1, in the scrambler mouse.</strong> Neuron 19: 239-249, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9292716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9292716</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80936-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9292716">Ware et al. (1997)</a> determined that the scrambler phenotype arises from mutations in mouse Dab1, a homolog of Drosophila dab. Dab encodes a phosphoprotein that binds nonreceptor tyrosine kinases and that has been implicated in neuronal development in flies. <a href="#16" class="mim-tip-reference" title="Sheldon, M., Rice, D. S., D'Arcangelo, G., Yoneshima, H., Nakajima, K., Mikoshiba, K., Howell, B. W., Cooper, J. A., Goldwitz, D., Curran, T. <strong>Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice.</strong> Nature 389: 730-733, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9338784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9338784</a>] [<a href="https://doi.org/10.1038/39601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9338784">Sheldon et al. (1997)</a> found that the yotari phenotype also results from a mutation in the Dab1 gene. Using in situ hybridization to embryonic day-13.5 mouse brain tissue, they demonstrated that Dab1 is expressed in neuronal populations exposed to reelin. The authors concluded that reelin and Dab1 function as signaling molecules that regulate cell positioning in the developing brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9292716+9338784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Howell, B. W., Hawkes, R., Soriano, P., Cooper, J. A. <strong>Neuronal position in the developing brain is regulated by mouse disabled-1.</strong> Nature 389: 733-737, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9338785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9338785</a>] [<a href="https://doi.org/10.1038/39607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9338785">Howell et al. (1997)</a> showed that targeted disruption of the mouse Dab1 gene disturbed neuronal layering in the cerebral cortex, hippocampus, and cerebellum, causing a reeler-like phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9338785" 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="#11" 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="Sanada, K., Gupta, A., Tsai, L.-H. <strong>Disabled-1-regulated adhesion of migrating neurons to radial glial fiber contributes to neuronal positioning during early corticogenesis.</strong> Neuron 42: 197-211, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15091337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15091337</a>] [<a href="https://doi.org/10.1016/s0896-6273(04)00222-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15091337">Sanada et al. (2004)</a> found that individual neurons in the cortex of Dab1-deficient scrambler mice exhibited an abnormal mode and tempo of radial migration, which was associated with impaired detachment from radial glial cells. Glial detachment depended on alpha-3 integrin signaling that was regulated by the phosphorylation state of Dab1 residues tyr220 and tyr232. <a href="#12" class="mim-tip-reference" title="Sanada, K., Gupta, A., Tsai, L.-H. <strong>Disabled-1-regulated adhesion of migrating neurons to radial glial fiber contributes to neuronal positioning during early corticogenesis.</strong> Neuron 42: 197-211, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15091337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15091337</a>] [<a href="https://doi.org/10.1016/s0896-6273(04)00222-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15091337">Sanada et al. (2004)</a> concluded that a functional link between DAB1 phosphorylation and ITGA3 signaling drives the timely detachment of migrating neurons from radial glial fibers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15091337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>1 Selected Example</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=603448[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 SPINOCEREBELLAR ATAXIA 37</strong>
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DAB1, 5-BP INS, ATTTC(n) REPEAT EXPANSION
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000495133" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000495133" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000495133</a>
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<p>In 35 affected individuals from 3 large, multigenerational kindreds (pedigrees M, G, and R) from southern Portugal with spinocerebellar ataxia-37 (SCA37; <a href="/entry/615945">615945</a>), <a href="#14" class="mim-tip-reference" title="Seixas, A. I., Loureiro, J. R., Costa, C., Ordonez-Ugalde, A., Marcelino, H., Oliveira,, C. L., Loureiro, J. L., Dhingra, A., Brandao, E., Cruz, V. T., Timoteo, A., Quintans, B., and 9 others. <strong>A pentanucleotide ATTTC repeat insertion in the non-coding region of DAB1, mapping to SCA37, causes spinocerebellar ataxia.</strong> Am. J. Hum. Genet. 101: 87-103, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28686858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28686858</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28686858[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.2017.06.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28686858">Seixas et al. (2017)</a> identified a heterozygous 5-bp ATTTC(n) insertion in the 5-prime UTR intron 3 of the DAB1 gene. The insertion was within a simple ATTTT/AAAAT repeat that localized to the polymorphic middle A-rich region of an AluJb sequence. The insertion mutation, which was found by a complex process of linkage analysis, next-generation sequencing, PCR analysis, Southern blot analysis, and Sanger sequencing, segregated with the disorder in the families. Six affected individuals from 3 additional Portuguese families with SCA37 also carried the pathogenic insertion. Haplotype analysis was consistent with a founder effect in all 6 families. The insertion was not detected in 520 control Portuguese chromosomes. The heterozygous ATTTC(n) insertion, ranging from 31 to 75 repeats, was always flanked by (ATTTT)n tracts larger than 58 repeats. In every disease allele, the insertion site was identical and placed in the middle of the normal ATTTT repeat, thus maintaining the pentanucleotide repeat structure. Sequence analysis of 260 control individuals showed that none contained the pathologic ATTTC repeat insertion. The distribution of normal ATTTT/AAAAT repeats in over 500 control subjects showed mostly alleles shorter than 30 repeats, with a rare group of larger alleles ranging from 30 to 400 repeats (about 7%). In vitro cellular expression studies showed that the ATTTC(n) insertion resulted in the formation of abnormal RNA aggregates with a nuclear localization. Injection of RNA containing the pathologic DAB1 repeat insertion into zebrafish embryos resulted in developmental defects and increased lethality. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28686858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Corral-Juan, M., Serrano-Munuera, C., Rabano, A., Cota-Gonzalez, D., Segarra-Roca, A., Ispierto, L., Cano-Orgaz, A. T., Adarmes, A. D., Mendez-del-Barrio, C., Jesus, S., Mir, P., Volpini, V., Alvarez-Ramo, R., Sanchez, I., Matilla-Duenas, A. <strong>Clinical, genetic and neuropathological characterization of spinocerebellar ataxia type 37.</strong> Brain 141: 1981-1997, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29939198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29939198</a>] [<a href="https://doi.org/10.1093/brain/awy137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29939198">Corral-Juan et al. (2018)</a> identified an unstable ATTTC(n) pentanucleotide repeat in the DAB1 gene in affected members of 4 unrelated families from the south of Spain with SCA37, including the large family (AT-901) previously reported by <a href="#15" class="mim-tip-reference" title="Serrano-Munuera, C., Corral-Juan, M., Stevanin, G., San Nicolas, H., Roig, C., Corral, J., Campos, B., de Jorge, L., Morcillo-Suarez, C., Navarro, A., Forlani, S., Durr, A., Kulisevsky, J., Brice, A., Sanchez, I., Volpini, V., Matilla-Duenas, A. <strong>New subtype of spinocerebellar ataxia with altered vertical eye movements mapping to chromosome 1p32.</strong> JAMA Neurol. 70: 764-771, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23700170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23700170</a>] [<a href="https://doi.org/10.1001/jamaneurol.2013.2311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23700170">Serrano-Munuera et al. (2013)</a>. Haplotype analysis suggested a founder effect. <a href="#2" class="mim-tip-reference" title="Corral-Juan, M., Serrano-Munuera, C., Rabano, A., Cota-Gonzalez, D., Segarra-Roca, A., Ispierto, L., Cano-Orgaz, A. T., Adarmes, A. D., Mendez-del-Barrio, C., Jesus, S., Mir, P., Volpini, V., Alvarez-Ramo, R., Sanchez, I., Matilla-Duenas, A. <strong>Clinical, genetic and neuropathological characterization of spinocerebellar ataxia type 37.</strong> Brain 141: 1981-1997, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29939198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29939198</a>] [<a href="https://doi.org/10.1093/brain/awy137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29939198">Corral-Juan et al. (2018)</a> stated that the repeat occurred in intron 11. Neuropathologic analysis of 2 patients showed that DAB1 was overexpressed in the cerebellum compared to controls, and DAB1 showed abnormal perisomatic and perinuclear punctate staining in remaining Purkinje cells. There was also dysregulated expression of DAB1 transcripts, reelin proteins, and upregulation of the reelin-DAB1 signaling pathway, which may adversely affect neuronal migration. <a href="#2" class="mim-tip-reference" title="Corral-Juan, M., Serrano-Munuera, C., Rabano, A., Cota-Gonzalez, D., Segarra-Roca, A., Ispierto, L., Cano-Orgaz, A. T., Adarmes, A. D., Mendez-del-Barrio, C., Jesus, S., Mir, P., Volpini, V., Alvarez-Ramo, R., Sanchez, I., Matilla-Duenas, A. <strong>Clinical, genetic and neuropathological characterization of spinocerebellar ataxia type 37.</strong> Brain 141: 1981-1997, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29939198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29939198</a>] [<a href="https://doi.org/10.1093/brain/awy137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29939198">Corral-Juan et al. (2018)</a> suggested that the mutation resulted in a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=29939198+23700170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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Bar, I., Tissir, F., Lambert de Rouvroit, C., De Backer, O., Goffinet, A. M.
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[<a href="https://doi.org/10.1074/jbc.M207178200" target="_blank">Full Text</a>]
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Corral-Juan, M., Serrano-Munuera, C., Rabano, A., Cota-Gonzalez, D., Segarra-Roca, A., Ispierto, L., Cano-Orgaz, A. T., Adarmes, A. D., Mendez-del-Barrio, C., Jesus, S., Mir, P., Volpini, V., Alvarez-Ramo, R., Sanchez, I., Matilla-Duenas, A.
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<strong>Clinical, genetic and neuropathological characterization of spinocerebellar ataxia type 37.</strong>
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Brain 141: 1981-1997, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29939198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29939198</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29939198" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awy137" target="_blank">Full Text</a>]
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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>
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Neuron 27: 33-44, 2000.
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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0896-6273(00)00007-6" target="_blank">Full Text</a>]
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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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[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://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10571241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0896-6273(00)80861-2" target="_blank">Full Text</a>]
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Honda, T., Nakajima, K.
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<strong>Mouse Disabled 1 (DAB1) is a nucleocytoplasmic shuttling protein.</strong>
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J. Biol. Chem. 281: 38951-38965, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17062576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17062576</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17062576" 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/10.1074/jbc.M609061200" target="_blank">Full Text</a>]
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Howell, B. W., Hawkes, R., Soriano, P., Cooper, J. A.
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<strong>Neuronal position in the developing brain is regulated by mouse disabled-1.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9338785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9338785</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9338785" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/39607" target="_blank">Full Text</a>]
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Huang, Y., Shah, V., Liu, T., Keshvara, L.
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[<a href="https://doi.org/10.1016/j.bbrc.2005.04.064" target="_blank">Full Text</a>]
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Lambert de Rouvroit, C., Goffinet, A. M.
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<strong>Cloning of human DAB1 and mapping to chromosome 1p31-p32.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9790777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9790777</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9790777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1998.5523" target="_blank">Full Text</a>]
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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: <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://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'})">related citations</a>]
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|
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[<a href="https://doi.org/10.1016/j.cell.2010.10.029" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="McAvoy2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
McAvoy, S., Zhu, Y., Perez, D. S., James, C. D., Smith, D. I.
|
|
<strong>Disabled-1 is a large common fragile site gene, inactivated in multiple cancers.</strong>
|
|
Genes Chromosomes Cancer 47: 165-174, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18008369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18008369</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18008369" 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/gcc.20519" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Rice2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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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.
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|
|
[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0896-6273(01)00436-6" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Sanada2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Sanada, K., Gupta, A., Tsai, L.-H.
|
|
<strong>Disabled-1-regulated adhesion of migrating neurons to radial glial fiber contributes to neuronal positioning during early corticogenesis.</strong>
|
|
Neuron 42: 197-211, 2004.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15091337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15091337</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15091337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0896-6273(04)00222-3" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Segarra2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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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.
|
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|
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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.aao2861" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Seixas2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Seixas, A. I., Loureiro, J. R., Costa, C., Ordonez-Ugalde, A., Marcelino, H., Oliveira,, C. L., Loureiro, J. L., Dhingra, A., Brandao, E., Cruz, V. T., Timoteo, A., Quintans, B., and 9 others.
|
|
<strong>A pentanucleotide ATTTC repeat insertion in the non-coding region of DAB1, mapping to SCA37, causes spinocerebellar ataxia.</strong>
|
|
Am. J. Hum. Genet. 101: 87-103, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28686858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28686858</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28686858[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=28686858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2017.06.007" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Serrano-Munuera2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Serrano-Munuera, C., Corral-Juan, M., Stevanin, G., San Nicolas, H., Roig, C., Corral, J., Campos, B., de Jorge, L., Morcillo-Suarez, C., Navarro, A., Forlani, S., Durr, A., Kulisevsky, J., Brice, A., Sanchez, I., Volpini, V., Matilla-Duenas, A.
|
|
<strong>New subtype of spinocerebellar ataxia with altered vertical eye movements mapping to chromosome 1p32.</strong>
|
|
JAMA Neurol. 70: 764-771, 2013.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23700170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23700170</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23700170" 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/10.1001/jamaneurol.2013.2311" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Sheldon1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sheldon, M., Rice, D. S., D'Arcangelo, G., Yoneshima, H., Nakajima, K., Mikoshiba, K., Howell, B. W., Cooper, J. A., Goldwitz, D., Curran, T.
|
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<strong>Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice.</strong>
|
|
Nature 389: 730-733, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9338784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9338784</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9338784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/39601" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Trommsdorff1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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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.
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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)80782-5" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Ware1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ware, M. L., Fox, J. W., Gonzalez, J. L., Davis, N. M., Lambert de Rouvroit, C., Russo, C. J., Chua, S. C., Jr., Goffinet, A. M., Walsh, C. A.
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<strong>Aberrant splicing of a mouse disabled homolog, mdab1, in the scrambler mouse.</strong>
|
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Neuron 19: 239-249, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9292716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9292716</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9292716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0896-6273(00)80936-8" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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Ada Hamosh - updated : 11/20/2018
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 08/23/2018<br>Cassandra L. Kniffin - updated : 07/27/2017<br>Patricia A. Hartz - updated : 02/16/2011<br>Patricia A. Hartz - updated : 1/13/2009<br>Patricia A. Hartz - updated : 12/7/2005<br>Patricia A. Hartz - updated : 5/12/2005<br>Dawn Watkins-Chow - updated : 10/31/2002<br>Dawn Watkins-Chow - updated : 11/25/2001<br>Stylianos E. Antonarakis - updated : 7/8/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Rebekah S. Rasooly : 1/19/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 03/21/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 09/11/2019<br>alopez : 11/20/2018<br>carol : 08/31/2018<br>ckniffin : 08/23/2018<br>carol : 07/28/2017<br>ckniffin : 07/27/2017<br>mgross : 02/16/2011<br>mgross : 1/16/2009<br>mgross : 1/16/2009<br>terry : 1/13/2009<br>wwang : 12/15/2005<br>wwang : 12/7/2005<br>wwang : 5/19/2005<br>wwang : 5/17/2005<br>terry : 5/12/2005<br>carol : 11/4/2002<br>tkritzer : 10/31/2002<br>tkritzer : 10/31/2002<br>carol : 11/25/2001<br>psherman : 7/9/1999<br>mgross : 7/8/1999<br>mgross : 7/8/1999<br>alopez : 1/19/1999
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
|
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<strong>*</strong> 603448
|
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</span>
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</h3>
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</div>
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<div>
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<h3>
|
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<span class="mim-font">
|
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DAB ADAPTOR PROTEIN 1; DAB1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
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</span>
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</p>
|
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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DISABLED, DROSOPHILA, HOMOLOG OF, 1
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: DAB1</em></strong>
|
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 719301002;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: 1p32.2-p32.1
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 1:56,994,778-58,546,726 </span>
|
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</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
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Phenotype
|
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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1p32.2-p32.1
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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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Spinocerebellar ataxia 37
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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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615945
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<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>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The reelin (RELN; 600514) signaling pathway plays a critical role in the correct positioning of neurons within the developing brain. Animal studies have shown that DAB1 serves as an intracellular adaptor that is tyrosine phosphorylated when reelin binds to the lipoprotein receptors VLDLR (192977) and APOER2 (LRP8; 602600) on the surface of neurons (Huang et al., 2005). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By RT-PCR of human embryonic brain RNA using degenerate primers based on mouse Dab1, Lambert de Rouvroit and Goffinet (1998) cloned human DAB1. The deduced 555-amino acid protein contains a putative N-terminal phosphotyrosine-binding (PTB) domain. DAB1 shares 96% overall amino acid identity with the 555-amino acid mouse Dab1 isoform, and the 2 proteins are identical over their first 271 amino acids. DAB1 shares significant similarity with Drosophila 'disabled' (dab). </p><p>By 5-prime RACE of human and mouse embryonic brain RNA, Bar et al. (2003) identified 6 alternative 5-prime UTRs for human DAB1 and 4 alternative 5-prime UTRs for mouse Dab1. Three 5-prime UTRs, which the authors called UTRs 1A, 1B, and 1D, are conserved between mouse and human. UTR 1B, which contains 7 exons in human and 10 exons in mouse, contains several upstream ORFs and numerous upstream ATG codons preceding the major translation initiation site, and some of the ORFs are conserved between mouse and human. RT-PCR of mouse tissues detected transcripts containing UTR 1B only in brain, whereas transcripts containing UTRs 1A and 1D were detected in brain, testis, kidney, and liver, but not in spleen, heart, or thymus. PCR analysis of mouse brain at various developmental stages revealed weak UTR 1B expression at embryonic days 11 and 12, and stronger expression at embryonic day 15, at birth, and in adult. </p><p>Using RT-PCR, McAvoy et al. (2008) found that DAB1 was expressed in all normal human tissues examined, including brain, breast, cervix, endometrium, prostate, and ovary. It was also expressed in cell lines derived from normal ovarian surface epithelium and normal breast epithelium. </p><p>Seixas et al. (2017) noted that the expression of DAB1 is very complex because it contains several alternative first exons that can result in transcripts with variable 5-prime UTRs. Various transcripts were found in multiple human central nervous system regions, including the cerebellum, and all showed higher expression in human fetal brain tissue compared to adult brain. </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>Bar et al. (2003) determined that the DAB1 gene spans more than 1.2 Mb. Exons 2 through 14 span more than 294 kb and contain the coding region for the major DAB1 isoform. Exon 15 contains the 3-prime UTR. Multiple 5-prime exons are spread over a 961-kb region and produce 6 alternative 5-prime UTRs. The most complex 5-prime UTR, UTR 1B, is made up of 7 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
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<p>By analysis of radiation hybrids, Lambert de Rouvroit and Goffinet (1998) mapped the DAB1 gene to chromosome 1p32-p31. This region shows homology of synteny with the segment of mouse chromosome 4 containing Dab1. </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>Studies in mice have shown that layering of neurons in the cerebral cortex and cerebellum requires Reln and Dab1 (see ANIMAL MODEL). By targeted disruption experiments in mice, Trommsdorff et al. (1999) showed that 2 cell surface receptors, Vldlr and Apoer2, 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 bound directly and specifically to the extracellular domains of Vldlr and ApoER2. Blockade of Vldlr and ApoER2 ligand binding correlated with loss of Reelin-induced Dab1 tyrosine phosphorylation. With Western blot analysis, they demonstrated that mice lacking either Reln or Vldlr and ApoER2 (Trommsdorff et al., 1999) exhibited 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>Using immunolabeling, Dulabon et al. (2000) detected coexpression of Dab1 and alpha-3 (ITGA3; 605025)-beta-1 (ITGB1; 135630) integrin receptor in mouse embryonic cortical neurons with overlapping subcellular localization. They also observed reduced levels of Dab1 protein and elevated expression of a Reln fragment in cerebral cortices of alpha-3-beta-1 integrin-deficient mice. Dulabon et al. (2000) concluded that reelin/alpha-3-beta-1 integrin interactions regulate Dab1 protein levels but not Dab1 phosphorylation. </p><p>Huang et al. (2005) stated that the PTB domain of mouse Dab1 binds to APP (104760)-type transmembrane receptors and to lipoprotein receptors. The PTB domain also exhibits a pleckstrin (PLEK; 173570) homology (PH) domain-like function, whereby it binds to phosphoinositides (PI), with lys45 being critical for binding to phosphatidylinositol-4,5-bisphosphate. Huang et al. (2005) found that PI binding targeted Dab1 to the membrane, where it was subject to basal phosphorylation independent of reelin, Vldlr, and Apoer2. This receptor-independent membrane targeting of Dab1 was required for interaction of Dab1 with the downstream signaling proteins Src (190090) and Crk (164762), and disruption of PI binding prevented reelin-induced Dab1 hyperphosphorylation. </p><p>Honda and Nakajima (2006) found that mouse Dab1 shuttled between the cytoplasm and nucleus. Inhibition of the Ran (601179)-GTP-dependent nuclear export protein Crm1 (XPO1; 602559) in a mouse neuroblastoma cell line resulted in nuclear accumulation of Dab1. Mutagenesis analysis revealed that Dab1 contains 2 leucine-rich nuclear export signal sequences and a bipartite nuclear localization signal sequence. Honda and Nakajima (2006) also showed that Dab1 interacted directly with Crm1 in a Ran-GTP-dependent manner. </p><p>McAvoy et al. (2008) found that DAB1 mRNA and protein expression was reduced in a variety of human cancers, especially in brain and endometrial cancers. Experimental overexpression of DAB1 in a human breast cancer cell line inhibited cell growth. </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>Segarra et al. (2018) found that the neuronal guidance cue reelin (600514) 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. APOE receptor 2 (602600) 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>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>In 35 affected individuals from 3 large, multigenerational kindreds (pedigrees M, G, and R) from southern Portugal with spinocerebellar ataxia-37 (SCA37; 615945), Seixas et al. (2017) identified a heterozygous 5-bp ATTTC(n) insertion in the 5-prime UTR intron 3 of the DAB1 gene. The insertion mutation, which was found by a complex process of linkage analysis, next-generation sequencing, PCR analysis, Southern blot analysis, and Sanger sequencing, segregated with the disorder in the families. Six affected individuals from 3 additional Portuguese families with SCA37 also carried the pathogenic insertion. Haplotype analysis was consistent with a founder effect in all 6 families. In vitro cellular expression studies showed that the ATTTC(n) insertion resulted in the formation of abnormal RNA aggregates with a nuclear localization. Injection of RNA containing the pathologic DAB1 repeat insertion into zebrafish embryos resulted in developmental defects and increased lethality. </p><p>In affected members of 4 unrelated families with SCA37, all from the same region in southern Spain, Corral-Juan et al. (2018) identified an unstable intronic ATTTC(n) pentanucleotide repeat within a noncoding regulatory region of the DAB1 gene. The ATTTC repeat ranged from 46 to 71 repeats, and there was a significant inverse correlation between repeat size and age at onset in males, but not in females. Neuropathologic analysis of 2 patients showed that DAB1 was overexpressed in the cerebellum compared to controls, and DAB1 showed abnormal perisomatic and perinuclear punctate staining in remaining Purkinje cells. There was also dysregulated expression of DAB1 transcripts, reelin proteins, and upregulation of the reelin-DAB1 signaling pathway, which may adversely affect neuronal migration. Corral-Juan et al. (2018) suggested that the mutation resulted in a gain of function. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Cortical neurons form in specialized proliferative regions deep in the brain and migrate past previously formed neurons to reach their proper layer. The laminar organization of multiple neuronal types in the cerebral cortex is required for normal cognitive function. The mouse 'reeler' mutation causes abnormal patterns of cortical neuronal migration and defects in cerebellar development and neuronal positioning in other brain regions. Reelin (RELN; 600514), the product of the gene mutant in reeler, is an extracellular protein secreted by pioneer neurons. The mouse 'scrambler' and 'yotari' recessive mutations exhibit a phenotype identical to that of reeler. Ware et al. (1997) determined that the scrambler phenotype arises from mutations in mouse Dab1, a homolog of Drosophila dab. Dab encodes a phosphoprotein that binds nonreceptor tyrosine kinases and that has been implicated in neuronal development in flies. Sheldon et al. (1997) found that the yotari phenotype also results from a mutation in the Dab1 gene. Using in situ hybridization to embryonic day-13.5 mouse brain tissue, they demonstrated that Dab1 is expressed in neuronal populations exposed to reelin. The authors concluded that reelin and Dab1 function as signaling molecules that regulate cell positioning in the developing brain. </p><p>Howell et al. (1997) showed that targeted disruption of the mouse Dab1 gene disturbed neuronal layering in the cerebral cortex, hippocampus, and cerebellum, causing a reeler-like phenotype. </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>Sanada et al. (2004) found that individual neurons in the cortex of Dab1-deficient scrambler mice exhibited an abnormal mode and tempo of radial migration, which was associated with impaired detachment from radial glial cells. Glial detachment depended on alpha-3 integrin signaling that was regulated by the phosphorylation state of Dab1 residues tyr220 and tyr232. Sanada et al. (2004) concluded that a functional link between DAB1 phosphorylation and ITGA3 signaling drives the timely detachment of migrating neurons from radial glial fibers. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>1 Selected Example):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 SPINOCEREBELLAR ATAXIA 37</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
DAB1, 5-BP INS, ATTTC(n) REPEAT EXPANSION
|
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<br />
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|
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ClinVar: RCV000495133
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|
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</span>
|
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</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 35 affected individuals from 3 large, multigenerational kindreds (pedigrees M, G, and R) from southern Portugal with spinocerebellar ataxia-37 (SCA37; 615945), Seixas et al. (2017) identified a heterozygous 5-bp ATTTC(n) insertion in the 5-prime UTR intron 3 of the DAB1 gene. The insertion was within a simple ATTTT/AAAAT repeat that localized to the polymorphic middle A-rich region of an AluJb sequence. The insertion mutation, which was found by a complex process of linkage analysis, next-generation sequencing, PCR analysis, Southern blot analysis, and Sanger sequencing, segregated with the disorder in the families. Six affected individuals from 3 additional Portuguese families with SCA37 also carried the pathogenic insertion. Haplotype analysis was consistent with a founder effect in all 6 families. The insertion was not detected in 520 control Portuguese chromosomes. The heterozygous ATTTC(n) insertion, ranging from 31 to 75 repeats, was always flanked by (ATTTT)n tracts larger than 58 repeats. In every disease allele, the insertion site was identical and placed in the middle of the normal ATTTT repeat, thus maintaining the pentanucleotide repeat structure. Sequence analysis of 260 control individuals showed that none contained the pathologic ATTTC repeat insertion. The distribution of normal ATTTT/AAAAT repeats in over 500 control subjects showed mostly alleles shorter than 30 repeats, with a rare group of larger alleles ranging from 30 to 400 repeats (about 7%). In vitro cellular expression studies showed that the ATTTC(n) insertion resulted in the formation of abnormal RNA aggregates with a nuclear localization. Injection of RNA containing the pathologic DAB1 repeat insertion into zebrafish embryos resulted in developmental defects and increased lethality. </p><p>Corral-Juan et al. (2018) identified an unstable ATTTC(n) pentanucleotide repeat in the DAB1 gene in affected members of 4 unrelated families from the south of Spain with SCA37, including the large family (AT-901) previously reported by Serrano-Munuera et al. (2013). Haplotype analysis suggested a founder effect. Corral-Juan et al. (2018) stated that the repeat occurred in intron 11. Neuropathologic analysis of 2 patients showed that DAB1 was overexpressed in the cerebellum compared to controls, and DAB1 showed abnormal perisomatic and perinuclear punctate staining in remaining Purkinje cells. There was also dysregulated expression of DAB1 transcripts, reelin proteins, and upregulation of the reelin-DAB1 signaling pathway, which may adversely affect neuronal migration. Corral-Juan et al. (2018) suggested that the mutation resulted in a gain of function. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bar, I., Tissir, F., Lambert de Rouvroit, C., De Backer, O., Goffinet, A. M.
|
|
<strong>The gene encoding Disabled-1 (DAB1), the intracellular adaptor of the reelin pathway, reveals unusual complexity in human and mouse.</strong>
|
|
J. Biol. Chem. 278: 5802-5812, 2003.
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[PubMed: 12446734]
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[Full Text: https://doi.org/10.1074/jbc.M207178200]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Corral-Juan, M., Serrano-Munuera, C., Rabano, A., Cota-Gonzalez, D., Segarra-Roca, A., Ispierto, L., Cano-Orgaz, A. T., Adarmes, A. D., Mendez-del-Barrio, C., Jesus, S., Mir, P., Volpini, V., Alvarez-Ramo, R., Sanchez, I., Matilla-Duenas, A.
|
|
<strong>Clinical, genetic and neuropathological characterization of spinocerebellar ataxia type 37.</strong>
|
|
Brain 141: 1981-1997, 2018.
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[PubMed: 29939198]
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[Full Text: https://doi.org/10.1093/brain/awy137]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
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.
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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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<li>
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<p class="mim-text-font">
|
|
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.
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[PubMed: 10571241]
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[Full Text: https://doi.org/10.1016/s0896-6273(00)80861-2]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Honda, T., Nakajima, K.
|
|
<strong>Mouse Disabled 1 (DAB1) is a nucleocytoplasmic shuttling protein.</strong>
|
|
J. Biol. Chem. 281: 38951-38965, 2006.
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[PubMed: 17062576]
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[Full Text: https://doi.org/10.1074/jbc.M609061200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Howell, B. W., Hawkes, R., Soriano, P., Cooper, J. A.
|
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<strong>Neuronal position in the developing brain is regulated by mouse disabled-1.</strong>
|
|
Nature 389: 733-737, 1997.
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[PubMed: 9338785]
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[Full Text: https://doi.org/10.1038/39607]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Huang, Y., Shah, V., Liu, T., Keshvara, L.
|
|
<strong>Signaling through Disabled 1 requires phosphoinositide binding.</strong>
|
|
Biochem. Biophys. Res. Commun. 331: 1460-1468, 2005.
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[PubMed: 15883038]
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[Full Text: https://doi.org/10.1016/j.bbrc.2005.04.064]
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</p>
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</li>
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McAvoy, S., Zhu, Y., Perez, D. S., James, C. D., Smith, D. I.
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<strong>Disabled-1 is a large common fragile site gene, inactivated in multiple cancers.</strong>
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Rice, D. S., Nusinowitz, S., Azimi, A. M., Martinez, A., Soriano, E., Curran, T.
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Sanada, K., Gupta, A., Tsai, L.-H.
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<strong>Disabled-1-regulated adhesion of migrating neurons to radial glial fiber contributes to neuronal positioning during early corticogenesis.</strong>
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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.
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<strong>Endothelial Dab1 signaling orchestrates neuro-glia-vessel communication in the central nervous system.</strong>
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Science 361: eaao2861, 2018. Note: Electronic Article.
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Seixas, A. I., Loureiro, J. R., Costa, C., Ordonez-Ugalde, A., Marcelino, H., Oliveira,, C. L., Loureiro, J. L., Dhingra, A., Brandao, E., Cruz, V. T., Timoteo, A., Quintans, B., and 9 others.
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Ware, M. L., Fox, J. W., Gonzalez, J. L., Davis, N. M., Lambert de Rouvroit, C., Russo, C. J., Chua, S. C., Jr., Goffinet, A. M., Walsh, C. A.
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