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<title>
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Entry
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- *608201 - CDK5 REGULATORY SUBUNIT-ASSOCIATED PROTEIN 2; CDK5RAP2
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- OMIM
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<p>
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<span class="h4">*608201</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/608201">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000136861;t=ENST00000349780" 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=55755" 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=608201" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000136861;t=ENST00000349780" 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_001011649,NM_001272039,NM_001410992,NM_001410993,NM_001410994,NM_018249,NR_073554,NR_073555,NR_073556,NR_073557,NR_073558,XM_006717185,XM_017014923,XM_047423587,XM_047423588,XM_047423589,XM_047423590,XM_047423591" 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_018249" 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=608201" 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=09740&isoform_id=09740_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/CDK5RAP2" 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/6456846,7023172,10438512,14042453,30911061,31873344,31873449,31873716,33988750,34365203,51536416,58535451,58535453,60219507,116283383,119607863,119607864,119607865,119607866,119607867,119607868,119607869,148921587,193783812,219520371,223459576,296439505,311643751,311643753,440309853,578817658,754296765,929654863,1034670694,2217377784,2217377786,2217377788,2217377791,2217377794,2287780779,2287780793,2287780878,2462625347,2462625349,2462625351,2462625353,2462625355,2462625357,2462625359" 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/Q96SN8" 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 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=55755" 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=ENSG00000136861;t=ENST00000349780" 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=CDK5RAP2" 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=CDK5RAP2" 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+55755" 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/CDK5RAP2" 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:55755" 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/55755" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr9&hgg_gene=ENST00000349780.9&hgg_start=120388875&hgg_end=120580167&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:18672" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:18672" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=608201[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=608201[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/CDK5RAP2/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/ENSG00000136861" 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=CDK5RAP2" 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=CDK5RAP2" 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=CDK5RAP2" 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=CDK5RAP2&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/PA38632" 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:18672" 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/FBgn0013765.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:2384875" 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/CDK5RAP2#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:2384875" 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/55755/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=55755" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-6392" 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://reactome.org/content/query?q=CDK5RAP2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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608201
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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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CDK5 REGULATORY SUBUNIT-ASSOCIATED PROTEIN 2; CDK5RAP2
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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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CENTROSOMAL PROTEIN, 215-KD; CEP215<br />
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KIAA1633
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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=CDK5RAP2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CDK5RAP2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/9/456?start=-3&limit=10&highlight=456">9q33.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:120388875-120580167&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">9:120,388,875-120,580,167</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>
|
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<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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9q33.2
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Microcephaly 3, primary, autosomal recessive
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<a href="/entry/604804"> 604804 </a>
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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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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/608201" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/608201" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>The CDK5RAP2 gene encodes a centrosomal protein that localizes to the spindle poles during mitosis (summary by <a href="#6" class="mim-tip-reference" title="Hassan, M. J., Khurshid, M., Azeem, Z., John, P., Ali, G., Chishti, M. S., Ahmad, W. <strong>Previously described sequence variant in CDK5RAP2 gene in a Pakistani family with autosomal recessive primary microcephaly.</strong> BMC Med. Genet. 8: 58, 2007. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17764569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17764569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17764569[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/10.1186/1471-2350-8-58" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17764569">Hassan et al., 2007</a> and <a href="#9" class="mim-tip-reference" title="Lizarraga, S. B., Margossian, S. P., Harris, M. H., Campagna, D. R., Han, A.-P., Blevins, S., Mudbhary, R., Barker, J. E., Walsh, C. A., Fleming, M. D. <strong>Cdk5rap2 regulates centrosome function and chromosome segregation in neuronal progenitors.</strong> Development 137: 1907-1917, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20460369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20460369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20460369[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/10.1242/dev.040410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20460369">Lizarraga et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17764569+20460369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="cloning" class="mim-anchor"></a>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Cloning and Expression</strong>
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<p>By sequencing clones obtained from a size-fractionated fetal brain cDNA library, <a href="#11" class="mim-tip-reference" title="Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.</strong> DNA Res. 7: 273-281, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10997877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10997877</a>] [<a href="https://doi.org/10.1093/dnares/7.4.271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10997877">Nagase et al. (2000)</a> cloned CDK5RAP2, which they designated KIAA1633. The deduced protein contains 1,561 amino acids. RT-PCR ELISA detected moderate to high expression of CDK5RAP2 in all tissues and specific brain regions examined. Highest levels were detected in skeletal muscle, fetal liver, brain, kidney, and ovary. Within specific brain regions, highest expression was detected in thalamus, corpus callosum, substantia nigra, hippocampus, and caudate nucleus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10997877" 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 NCK5A (CDK5R1; <a href="/entry/603460">603460</a>) as bait in a yeast 2-hybrid screen of a brain cDNA library, <a href="#2" class="mim-tip-reference" title="Ching, Y. P., Qi, Z., Wang, J. H. <strong>Cloning of three novel neuronal Cdk5 activator binding proteins.</strong> Gene 242: 285-294, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10721722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10721722</a>] [<a href="https://doi.org/10.1016/s0378-1119(99)00499-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10721722">Ching et al. (2000)</a> obtained a partial clone of CDK5RAP2, which they designated C48. Northern blot analysis detected expression in all tissues examined, with highest levels in heart and skeletal muscle. <a href="#2" class="mim-tip-reference" title="Ching, Y. P., Qi, Z., Wang, J. H. <strong>Cloning of three novel neuronal Cdk5 activator binding proteins.</strong> Gene 242: 285-294, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10721722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10721722</a>] [<a href="https://doi.org/10.1016/s0378-1119(99)00499-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10721722">Ching et al. (2000)</a> also cloned full-length rat Cdk5rap2 from a brain cDNA library. The deduced 217-amino acid rat protein has a serine-rich N terminus and shares a region of homology with restin (<a href="/entry/179838">179838</a>), an intermediate filament-associated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10721722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Evans, P. D., Vallender, E. J., Lahn, B. T. <strong>Molecular evolution of the brain size regulator genes CDK5RAP2 and CENPJ.</strong> Gene 375: 75-79, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16631324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16631324</a>] [<a href="https://doi.org/10.1016/j.gene.2006.02.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16631324">Evans et al. (2006)</a> stated that the CDK5RAP2 protein contains 2 structural maintenance of chromosomes (SMC; see <a href="/entry/608685">608685</a>) domains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16631324" 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="Graser, S., Stierhof, Y.-D., Nigg, E. A. <strong>Cep68 and Cep215 (Cdk5rap2) are required for centrosome cohesion.</strong> J. Cell. Sci. 120: 4321-4331, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18042621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18042621</a>] [<a href="https://doi.org/10.1242/jcs.020248" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18042621">Graser et al. (2007)</a> reported that CEP215 encodes 2 isoforms containing 1,893 and 1,814 amino acids. Both isoforms have an N-terminal microtubule-association domain and 10 coiled-coil domains. Compared with the long isoform, the short isoform has a deletion near the C terminus that involves part of coiled-coil domain-9. Immunohistochemical and immunoelectron microscopic analyses of U2OS cells showed CEP215 at centriolar cylinders. CEP215 staining persisted on centrosomes throughout the cell cycle. Western blot analysis of HeLa, U2OS, and 293T cells detected CEP215 at an apparent molecular mass of approximately 210 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18042621" 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>Gene Structure</strong>
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<p><a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Springell, K., Lizarraga, S., Scott, S., Higgins, J., Hampshire, D. J., Morrison, E. E., Leal, G. F., Silva, E. O., Costa, S. M. R., Baralle, D., Raponi, M., Karbani, G., Rashid, Y., Jafri, H., Bennett, C., Corry, P., Walsh, C. A., Woods, C. G. <strong>A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size.</strong> Nature Genet. 37: 353-355, 2005. Note: Erratum: Nature Genet. 37: 555 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15793586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15793586</a>] [<a href="https://doi.org/10.1038/ng1539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15793586">Bond et al. (2005)</a> stated that the CDK5RAP2 gene contains 34 exons. <a href="#3" class="mim-tip-reference" title="Evans, P. D., Vallender, E. J., Lahn, B. T. <strong>Molecular evolution of the brain size regulator genes CDK5RAP2 and CENPJ.</strong> Gene 375: 75-79, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16631324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16631324</a>] [<a href="https://doi.org/10.1016/j.gene.2006.02.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16631324">Evans et al. (2006)</a> determined that the CDK5RAP2 gene contains 38 exons and spans 190 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16631324+15793586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Graser, S., Stierhof, Y.-D., Nigg, E. A. <strong>Cep68 and Cep215 (Cdk5rap2) are required for centrosome cohesion.</strong> J. Cell. Sci. 120: 4321-4331, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18042621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18042621</a>] [<a href="https://doi.org/10.1242/jcs.020248" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18042621">Graser et al. (2007)</a> stated that the CDK5RAP2 gene maps to chromosome 9q33.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18042621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Ching, Y. P., Qi, Z., Wang, J. H. <strong>Cloning of three novel neuronal Cdk5 activator binding proteins.</strong> Gene 242: 285-294, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10721722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10721722</a>] [<a href="https://doi.org/10.1016/s0378-1119(99)00499-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10721722">Ching et al. (2000)</a> determined that rat Cdk5rap2 was phosphorylated by Cdk5 kinase (<a href="/entry/123831">123831</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10721722" 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 a small interfering RNA screen, <a href="#5" class="mim-tip-reference" title="Graser, S., Stierhof, Y.-D., Nigg, E. A. <strong>Cep68 and Cep215 (Cdk5rap2) are required for centrosome cohesion.</strong> J. Cell. Sci. 120: 4321-4331, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18042621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18042621</a>] [<a href="https://doi.org/10.1242/jcs.020248" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18042621">Graser et al. (2007)</a> found that depletion of CNAP1 (CEP2; <a href="/entry/609689">609689</a>), rootletin (CROCC; <a href="/entry/615776">615776</a>), pericentrin (PCNT; <a href="/entry/605925">605925</a>), CEP68 (<a href="/entry/616889">616889</a>), or CEP215 reduced centrosome cohesion and caused centrosome splitting in U2OS, A549, and RPE1 cells. Depletion of CNAP1 and rootletin produced the most severe phenotype. Depletion of pericentrin caused loss of CEP215 from centrioles, but depletion of CEP215 had no effect on pericentrin. <a href="#5" class="mim-tip-reference" title="Graser, S., Stierhof, Y.-D., Nigg, E. A. <strong>Cep68 and Cep215 (Cdk5rap2) are required for centrosome cohesion.</strong> J. Cell. Sci. 120: 4321-4331, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18042621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18042621</a>] [<a href="https://doi.org/10.1242/jcs.020248" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18042621">Graser et al. (2007)</a> concluded that CEP215 and pericentrin functionally interact and influence centrosome cohesion through an indirect mechanism independent of CNAP1, rootletin, and CEP68. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18042621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., Homfray, T., Penninger, J. M., Jackson, A. P., Knoblich, J. A. <strong>Cerebral organoids model human brain development and microcephaly.</strong> Nature 501: 373-379, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23995685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23995685</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23995685[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23995685">Lancaster et al. (2013)</a> developed a human pluripotent stem cell-derived 3-dimensional organoid culture system, termed cerebral organoids, that develop various discrete, although interdependent, brain regions. These included a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids recapitulated features of human cortical development, namely, characteristic progenitor zone organization with abundant outer radial glial stem cells. <a href="#8" class="mim-tip-reference" title="Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., Homfray, T., Penninger, J. M., Jackson, A. P., Knoblich, J. A. <strong>Cerebral organoids model human brain development and microcephaly.</strong> Nature 501: 373-379, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23995685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23995685</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23995685[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23995685">Lancaster et al. (2013)</a> used RNA interference and patient-specific induced pluripotent stem cells to model microcephaly caused by deficiency of CDK5RAP2 (MCPH3; <a href="/entry/604804">604804</a>), a disorder that has been difficult to recapitulate in mice. <a href="#8" class="mim-tip-reference" title="Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., Homfray, T., Penninger, J. M., Jackson, A. P., Knoblich, J. A. <strong>Cerebral organoids model human brain development and microcephaly.</strong> Nature 501: 373-379, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23995685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23995685</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23995685[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23995685">Lancaster et al. (2013)</a> demonstrated premature neuronal differentiation in patient organoids, a defect that could help to explain the disease phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23995685" 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 a proximity interaction assay with U2OS cells, <a href="#4" class="mim-tip-reference" title="Firat-Karalar, E., Rauniyar, N., Yates, J. R., III, Stearns, T. <strong>Proximity interactions among centrosome components identify regulators of centriole duplication.</strong> Curr. Biol. 24: 664-670, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24613305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24613305</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24613305[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.cub.2014.01.067" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24613305">Firat-Karalar et al. (2014)</a> found that full-length CEP152 (<a href="/entry/613529">613529</a>) interacted with CDK5RAP2. Coimmunoprecipitation analysis in HEK293T cells confirmed direct interaction between CEP152 and CDK5RAP2. Depletion of CEP152 reduced centrosome localization of CDK5RAP2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24613305" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a Pakistani family with autosomal recessive primary microcephaly-3 (MCPH3; <a href="/entry/604804">604804</a>), <a href="#10" class="mim-tip-reference" title="Moynihan, L., Jackson, A. P., Roberts, E., Karbani, G., Lewis, I., Corry, P., Turner, G., Mueller, R. F., Lench, N. J., Woods, C. G. <strong>A third novel locus for primary autosomal recessive microcephaly maps to chromosome 9q34.</strong> Am. J. Hum. Genet. 66: 724-727, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677332</a>] [<a href="https://doi.org/10.1086/302777" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677332">Moynihan et al. (2000)</a> mapped the disorder to chromosome 9q34 by autozygosity mapping. <a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Springell, K., Lizarraga, S., Scott, S., Higgins, J., Hampshire, D. J., Morrison, E. E., Leal, G. F., Silva, E. O., Costa, S. M. R., Baralle, D., Raponi, M., Karbani, G., Rashid, Y., Jafri, H., Bennett, C., Corry, P., Walsh, C. A., Woods, C. G. <strong>A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size.</strong> Nature Genet. 37: 353-355, 2005. Note: Erratum: Nature Genet. 37: 555 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15793586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15793586</a>] [<a href="https://doi.org/10.1038/ng1539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15793586">Bond et al. (2005)</a> used a positional cloning strategy to identify genes in this region in 2 families, including the one previously described by <a href="#10" class="mim-tip-reference" title="Moynihan, L., Jackson, A. P., Roberts, E., Karbani, G., Lewis, I., Corry, P., Turner, G., Mueller, R. F., Lench, N. J., Woods, C. G. <strong>A third novel locus for primary autosomal recessive microcephaly maps to chromosome 9q34.</strong> Am. J. Hum. Genet. 66: 724-727, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677332</a>] [<a href="https://doi.org/10.1086/302777" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677332">Moynihan et al. (2000)</a>. Genotyping polymorphic microsatellite markers in the 2 families narrowed the region to 2.2 Mb. Bioinformatic analysis of the region identified CDK5RAP2 as a likely candidate. A homozygous mutation in the CDK5RAP2 gene was identified in affected members of each of the 2 families (<a href="#0001">608201.0001</a>-<a href="#0002">608201.0002</a>, respectively). Each mutation was absent from 380 northern Pakistani control chromosomes, showed the expected disease segregation in families, and was not present in chimpanzee, gorilla, orangutan, gibbon, mouse, or rat. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10677332+15793586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 6-year-old girl, born of consanguineous Somali parents, with MCPH3, <a href="#13" class="mim-tip-reference" title="Pagnamenta, A. T., Murray, J. E., Yoon, G., Sadighi Akha, E., Harrison, V., Bicknell, L. S., Ajilogba, K., Stewart, H., Kini, U., Taylor, J. C., Keays, D. A., Jackson, A. P., Knight, S. J. L. <strong>A novel nonsense CDK5RAP2 mutation in a Somali child with primary microcephaly and sensorineural hearing loss.</strong> Am. J. Med. Genet. 158A: 2577-2582, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22887808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22887808</a>] [<a href="https://doi.org/10.1002/ajmg.a.35558" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22887808">Pagnamenta et al. (2012)</a> identified a homozygous truncating mutation in the CDK5RAP2 gene (E234X; <a href="#0003">608201.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22887808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with MCPH3 and a simplified gyral pattern on brain imaging, <a href="#8" class="mim-tip-reference" title="Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., Homfray, T., Penninger, J. M., Jackson, A. P., Knoblich, J. A. <strong>Cerebral organoids model human brain development and microcephaly.</strong> Nature 501: 373-379, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23995685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23995685</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23995685[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23995685">Lancaster et al. (2013)</a> identified compound heterozygous truncating mutations in the CDK5RAP2 gene (<a href="#0004">608201.0004</a> and <a href="#0005">608201.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23995685" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 6-year-old girl of Caucasian and Cherokee ancestry with MCPH3 and normal brain imaging, <a href="#14" class="mim-tip-reference" title="Tan, C. A., Topper, S., Melver, C. W., Stein, J., Reeder, A., Arndt, K., Das, S. <strong>The first case of CDK5RAP2-related primary microcephaly in a non-consanguineous patient identified by next generation sequencing.</strong> Brain Dev. 36: 351-355, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23726037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23726037</a>] [<a href="https://doi.org/10.1016/j.braindev.2013.05.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23726037">Tan et al. (2014)</a> identified compound heterozygous mutations in the CDK5RAP2 gene (<a href="#0006">608201.0006</a> and <a href="#0007">608201.0007</a>). The mutations were found by next-generation sequencing of targeted microcephaly genes. The girl was 1 of triplets; the other 2 sisters were unaffected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23726037" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an 11-year-old boy with MCPH3, <a href="#12" class="mim-tip-reference" title="Pagnamenta, A. T., Howard, M. F., Knight, S. J. L., Keays, D. A., Quaghebeur, G., Taylor, J. C., Kini,, U. <strong>Activation of an exonic splice-donor site in exon 30 of CDK5RAP2 in a patient with severe microcephaly and pigmentary abnormalities.</strong> Clin. Case Rep. 4: 952-956, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27761245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27761245</a>] [<a href="https://doi.org/10.1002/ccr3.663" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27761245">Pagnamenta et al. (2016)</a> identified compound heterozygous mutations in the CDK5RAP2 gene (<a href="#0008">608201.0008</a> and <a href="#0009">608201.0009</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27761245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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In 3 adult sibs, born of unrelated French Canadian parents, with isolated agenesis of the corpus callosum (see <a href="/entry/217990">217990</a>), <a href="#7" class="mim-tip-reference" title="Jouan, L., Ouled Amar Bencheikh, B., Daoud, H., Dionne-Laporte, A., Dobrzeniecka, S., Spiegelman, D., Rochefort, D., Hince, P., Szuto, A., Lassonde, M., Barbelanne, M., Tsang, W. Y., Dion, P. A., Theoret, H., Rouleau, G. A. <strong>Exome sequencing identifies recessive CDK5RAP2 variants in patients with isolated agenesis of corpus callosum.</strong> Europ. J. Hum. Genet. 24: 607-610, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26197979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26197979</a>] [<a href="https://doi.org/10.1038/ejhg.2015.156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26197979">Jouan et al. (2016)</a> identified compound heterozygous missense variants in the CDK5RAP2 gene (NM_018249.5): a c.280G-C transversion, resulting in a gly94-to-arg (G94R) substitution, and a c.3695A-G transition, resulting in an asn1232-to-ser (N1232S) substitution. The variants, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both variants affected highly conserved nucleotides. G94R was found in 2 of 288 unaffected controls, but neither homozygous nor compound heterozygous variants were found. Both variants were present at low frequencies in the ExAC database (G94R at 8.237 x 10(-6), N1232S at 8.238 x 10(-6)), but were not found in the dbSNP (build 132), 1000 Genomes Project, or Exome Variant Server databases. Lymphoblastoid cells from 1 of the patients showed biallelic expression of the variants; functional studies of the variants were not performed. <a href="#7" class="mim-tip-reference" title="Jouan, L., Ouled Amar Bencheikh, B., Daoud, H., Dionne-Laporte, A., Dobrzeniecka, S., Spiegelman, D., Rochefort, D., Hince, P., Szuto, A., Lassonde, M., Barbelanne, M., Tsang, W. Y., Dion, P. A., Theoret, H., Rouleau, G. A. <strong>Exome sequencing identifies recessive CDK5RAP2 variants in patients with isolated agenesis of corpus callosum.</strong> Europ. J. Hum. Genet. 24: 607-610, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26197979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26197979</a>] [<a href="https://doi.org/10.1038/ejhg.2015.156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26197979">Jouan et al. (2016)</a> suggested that hypomorphic CDK5RAP2 variants with residual function may predispose to agenesis of the corpus callosum, while more detrimental loss-of-function variants may result in the more severe phenotype of microcephaly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26197979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The mouse Hertwig's anemia (an) mutant shows peripheral blood cytopenias, spontaneous aneuploidy, and a predisposition to hematopoietic tumors. <a href="#9" class="mim-tip-reference" title="Lizarraga, S. B., Margossian, S. P., Harris, M. H., Campagna, D. R., Han, A.-P., Blevins, S., Mudbhary, R., Barker, J. E., Walsh, C. A., Fleming, M. D. <strong>Cdk5rap2 regulates centrosome function and chromosome segregation in neuronal progenitors.</strong> Development 137: 1907-1917, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20460369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20460369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20460369[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/10.1242/dev.040410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20460369">Lizarraga et al. (2010)</a> found that the 'an' mutation was a homozygous mutation in the Cdk5rap2 gene that causes a deletion of exon 4. In addition to the hematopoietic phenotype, the mutant mice showed microcephaly with hypoplasia of several brain regions, including the cortex and hippocampus. Neuronal progenitors from the mutant mice showed proliferative and survival defects: they exited the cell cycle prematurely and many underwent apoptosis. These defects were associated with impaired mitotic progression coupled with abnormal mitotic spindle pole number and mitotic orientation. These findings suggested that the reduction in brain size observed in humans with mutations in CDK5RAP2 is associated with impaired centrosomal function and with changes in mitotic spindle orientation during the proliferation of neuronal progenitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20460369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>9 Selected Examples</a>):</strong>
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<a href="/allelicVariants/608201" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=608201[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 MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs199422126 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199422126;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs199422126?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199422126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs199422126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002594" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002594" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002594</a>
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<p>In affected members of a Pakistani family with autosomal recessive primary microcephaly-3 (MCPH3; <a href="/entry/604804">604804</a>) previously described by <a href="#10" class="mim-tip-reference" title="Moynihan, L., Jackson, A. P., Roberts, E., Karbani, G., Lewis, I., Corry, P., Turner, G., Mueller, R. F., Lench, N. J., Woods, C. G. <strong>A third novel locus for primary autosomal recessive microcephaly maps to chromosome 9q34.</strong> Am. J. Hum. Genet. 66: 724-727, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677332</a>] [<a href="https://doi.org/10.1086/302777" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677332">Moynihan et al. (2000)</a>, <a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Springell, K., Lizarraga, S., Scott, S., Higgins, J., Hampshire, D. J., Morrison, E. E., Leal, G. F., Silva, E. O., Costa, S. M. R., Baralle, D., Raponi, M., Karbani, G., Rashid, Y., Jafri, H., Bennett, C., Corry, P., Walsh, C. A., Woods, C. G. <strong>A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size.</strong> Nature Genet. 37: 353-355, 2005. Note: Erratum: Nature Genet. 37: 555 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15793586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15793586</a>] [<a href="https://doi.org/10.1038/ng1539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15793586">Bond et al. (2005)</a> identified a homozygous 243T-A transversion in exon 4 of the CDK5RAP2 gene, resulting in a ser81-to-ter (S81X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10677332+15793586" 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 4 sibs, born of consanguineous Pakistani parents of Kashmiri origin, with MCPH3, <a href="#6" class="mim-tip-reference" title="Hassan, M. J., Khurshid, M., Azeem, Z., John, P., Ali, G., Chishti, M. S., Ahmad, W. <strong>Previously described sequence variant in CDK5RAP2 gene in a Pakistani family with autosomal recessive primary microcephaly.</strong> BMC Med. Genet. 8: 58, 2007. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17764569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17764569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17764569[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/10.1186/1471-2350-8-58" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17764569">Hassan et al. (2007)</a> identified a homozygous c.246T-A transversion in the CDK5RAP2 gene, resulting in a tyr82-to-ter (Y82X) substitution. The patients had a head circumference of -4 to -7 SD and mental retardation. The mutation was found by homozygosity mapping and candidate gene analysis, segregated with the disorder in the family, and was not present in 200 control chromosomes. <a href="#6" class="mim-tip-reference" title="Hassan, M. J., Khurshid, M., Azeem, Z., John, P., Ali, G., Chishti, M. S., Ahmad, W. <strong>Previously described sequence variant in CDK5RAP2 gene in a Pakistani family with autosomal recessive primary microcephaly.</strong> BMC Med. Genet. 8: 58, 2007. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17764569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17764569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17764569[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/10.1186/1471-2350-8-58" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17764569">Hassan et al. (2007)</a> stated that this was the same mutation as that reported by <a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Springell, K., Lizarraga, S., Scott, S., Higgins, J., Hampshire, D. J., Morrison, E. E., Leal, G. F., Silva, E. O., Costa, S. M. R., Baralle, D., Raponi, M., Karbani, G., Rashid, Y., Jafri, H., Bennett, C., Corry, P., Walsh, C. A., Woods, C. G. <strong>A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size.</strong> Nature Genet. 37: 353-355, 2005. Note: Erratum: Nature Genet. 37: 555 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15793586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15793586</a>] [<a href="https://doi.org/10.1038/ng1539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15793586">Bond et al. (2005)</a>, and postulated a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17764569+15793586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE</strong>
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CDK5RAP2, IVS26AS, A-G, -15
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906274 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906274;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387906274?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906274" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906274" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002595" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002595" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002595</a>
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<p>In affected members of a Pakistani family with autosomal recessive primary microcephaly-3 (MCPH3; <a href="/entry/604804">604804</a>), <a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Springell, K., Lizarraga, S., Scott, S., Higgins, J., Hampshire, D. J., Morrison, E. E., Leal, G. F., Silva, E. O., Costa, S. M. R., Baralle, D., Raponi, M., Karbani, G., Rashid, Y., Jafri, H., Bennett, C., Corry, P., Walsh, C. A., Woods, C. G. <strong>A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size.</strong> Nature Genet. 37: 353-355, 2005. Note: Erratum: Nature Genet. 37: 555 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15793586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15793586</a>] [<a href="https://doi.org/10.1038/ng1539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15793586">Bond et al. (2005)</a> identified a homozygous A-to-G transition at position -15 of intron 26 of the CDK5RAP2 gene, resulting in a new splice acceptor site with the addition of 4 new amino acids and a premature stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15793586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122971 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122971;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs398122971" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs398122971" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 6-year-old girl, born of consanguineous Somali parents, with autosomal recessive primary microcephaly-3 (MCPH3; <a href="/entry/604804">604804</a>), <a href="#13" class="mim-tip-reference" title="Pagnamenta, A. T., Murray, J. E., Yoon, G., Sadighi Akha, E., Harrison, V., Bicknell, L. S., Ajilogba, K., Stewart, H., Kini, U., Taylor, J. C., Keays, D. A., Jackson, A. P., Knight, S. J. L. <strong>A novel nonsense CDK5RAP2 mutation in a Somali child with primary microcephaly and sensorineural hearing loss.</strong> Am. J. Med. Genet. 158A: 2577-2582, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22887808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22887808</a>] [<a href="https://doi.org/10.1002/ajmg.a.35558" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22887808">Pagnamenta et al. (2012)</a> identified a homozygous c.700G-T transversion in exon 8 of the CDK5RAP2 gene, resulting in a glu234-to-ter (E234X) substitution. The mutation was not found in over 5,000 Caucasian and African American samples in the Exome Variant Server database. The patient had delayed psychomotor development, microcephaly (-8.9 SD), and mild muscular hypotonia. She was diagnosed at age 3 years 10 months with moderate to severe sensorineural hearing loss, which may have been due to another genetic defect given the consanguinity in the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22887808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs374351172 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs374351172;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs374351172?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs374351172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs374351172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000076923 OR RCV001311021 OR RCV003398664" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000076923, RCV001311021, RCV003398664" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000076923...</a>
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<p>In a patient with autosomal recessive primary microcephaly-3 (MCPH3; <a href="/entry/604804">604804</a>), <a href="#8" class="mim-tip-reference" title="Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., Homfray, T., Penninger, J. M., Jackson, A. P., Knoblich, J. A. <strong>Cerebral organoids model human brain development and microcephaly.</strong> Nature 501: 373-379, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23995685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23995685</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23995685[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23995685">Lancaster et al. (2013)</a> identified compound heterozygous mutations in the CDK5RAP2 gene: a c.4546G-T transversion resulting in a glu1516-to-ter (E1516X) substitution, and a c.4672C-T transition resulting in an arg1558-to-ter (R1558X; <a href="#0005">608201.0005</a>) substitution. Each unaffected parent was heterozygous for 1 of the mutations. CDK5RAP2 protein was undetectable in patient cell lysates. The patient had severe microcephaly (-13.2 SD), short stature (-6.7 SD), simplified gyral pattern on brain imaging, delayed psychomotor development, and mixed conductive/sensorineural hearing loss. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23995685" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs373278668 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs373278668;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs373278668?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs373278668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs373278668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the arg1558-to-ter (R1558X) mutation in the CDK5RAP2 gene that was found in compound heterozygous state in a patient with autosomal recessive primary microcephaly-3 (MCPH3; <a href="/entry/604804">604804</a>) by <a href="#8" class="mim-tip-reference" title="Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., Homfray, T., Penninger, J. M., Jackson, A. P., Knoblich, J. A. <strong>Cerebral organoids model human brain development and microcephaly.</strong> Nature 501: 373-379, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23995685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23995685</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23995685[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23995685">Lancaster et al. (2013)</a>, see <a href="#0004">608201.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23995685" 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>.0006 MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs587783393 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587783393;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs587783393?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587783393" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs587783393" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000115025 OR RCV002515791" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000115025, RCV002515791" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000115025...</a>
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<p>In a 6-year-old girl with autosomal recessive primary microcephaly-3 (MCPH3; <a href="/entry/604804">604804</a>), <a href="#14" class="mim-tip-reference" title="Tan, C. A., Topper, S., Melver, C. W., Stein, J., Reeder, A., Arndt, K., Das, S. <strong>The first case of CDK5RAP2-related primary microcephaly in a non-consanguineous patient identified by next generation sequencing.</strong> Brain Dev. 36: 351-355, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23726037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23726037</a>] [<a href="https://doi.org/10.1016/j.braindev.2013.05.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23726037">Tan et al. (2014)</a> identified compound heterozygous mutations in the CDK5RAP2 gene: a 5-bp deletion (c.524_528del) in exon 7, resulting in a frameshift and premature termination (Gln175ArgfsTer42), and a G-to-A transition in intron 26 (c.4005-1G-A; <a href="#0007">608201.0007</a>), predicted to result in a splicing defect. Each unaffected parent was heterozygous for 1 of the mutations, which were found by next-generation sequencing of targeted microcephaly genes and confirmed by Sanger sequencing. The mother of the patient was of northern European descent and the father was Caucasian with Cherokee ancestry. The girl was 1 of triplets; the other 2 sisters were unaffected. The patient had severe microcephaly (-8.9 SD) and developmental delay, but brain MRI showed no structural abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23726037" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs587783387 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587783387;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs587783387?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587783387" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs587783387" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the splice site mutation in the CDK5RAP2 gene (c.4005-1G-A) that was found in compound heterozygous state in a patient with autosomal recessive primary microcephaly-3 (MCPH3; <a href="/entry/604804">604804</a>) by <a href="#14" class="mim-tip-reference" title="Tan, C. A., Topper, S., Melver, C. W., Stein, J., Reeder, A., Arndt, K., Das, S. <strong>The first case of CDK5RAP2-related primary microcephaly in a non-consanguineous patient identified by next generation sequencing.</strong> Brain Dev. 36: 351-355, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23726037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23726037</a>] [<a href="https://doi.org/10.1016/j.braindev.2013.05.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23726037">Tan et al. (2014)</a>, see <a href="#0006">608201.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23726037" 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>.0008 MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs869025200 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869025200;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs869025200" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs869025200" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000207398" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000207398" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000207398</a>
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<p>In an 11-year-old boy (patient BRC081), born of unrelated Caucasian parents, with autosomal recessive primary microcephaly-3 (MCPH3; <a href="/entry/604804">604804</a>), <a href="#12" class="mim-tip-reference" title="Pagnamenta, A. T., Howard, M. F., Knight, S. J. L., Keays, D. A., Quaghebeur, G., Taylor, J. C., Kini,, U. <strong>Activation of an exonic splice-donor site in exon 30 of CDK5RAP2 in a patient with severe microcephaly and pigmentary abnormalities.</strong> Clin. Case Rep. 4: 952-956, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27761245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27761245</a>] [<a href="https://doi.org/10.1002/ccr3.663" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27761245">Pagnamenta et al. (2016)</a> identified compound heterozygous mutations in the CDK5RAP2 gene: a G-to-C transversion (c.4604+1G-C, NM_018249.5) in exon 30, predicted to alter a splice site, and a 1-bp deletion (c.3097delG; <a href="#0009">608201.0009</a>) in exon 23, predicted to result in a frameshift and premature termination (Val1033fsTer41). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the ExAC database. Analysis of patient cells showed that c.4604+1G-C mutation resulted in alternative use of a cryptic exonic splice donor site, which would result in premature termination (Val1526fsTer15). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27761245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs747831095 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs747831095;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs747831095?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs747831095" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs747831095" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000207363 OR RCV002517035 OR RCV003556239" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000207363, RCV002517035, RCV003556239" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000207363...</a>
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<p>For discussion of the 1-bp deletion (c.3097delG, NM_018249.5) in the CDK5RAP2 gene, predicted to result in a frameshift and premature termination (Val1033fsTer41), that was found in compound heterozygous state in a patient with autosomal recessive primary microcephaly-3 (MCPH3; <a href="/entry/604804">604804</a>) by <a href="#12" class="mim-tip-reference" title="Pagnamenta, A. T., Howard, M. F., Knight, S. J. L., Keays, D. A., Quaghebeur, G., Taylor, J. C., Kini,, U. <strong>Activation of an exonic splice-donor site in exon 30 of CDK5RAP2 in a patient with severe microcephaly and pigmentary abnormalities.</strong> Clin. Case Rep. 4: 952-956, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27761245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27761245</a>] [<a href="https://doi.org/10.1002/ccr3.663" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27761245">Pagnamenta et al. (2016)</a>, see <a href="#0008">608201.0008</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27761245" 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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Pagnamenta, A. T., Howard, M. F., Knight, S. J. L., Keays, D. A., Quaghebeur, G., Taylor, J. C., Kini,, U.
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<strong>Activation of an exonic splice-donor site in exon 30 of CDK5RAP2 in a patient with severe microcephaly and pigmentary abnormalities.</strong>
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Clin. Case Rep. 4: 952-956, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27761245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27761245</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27761245" 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/ccr3.663" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22887808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22887808</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22887808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.35558" target="_blank">Full Text</a>]
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<a id="Tan2014" class="mim-anchor"></a>
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Tan, C. A., Topper, S., Melver, C. W., Stein, J., Reeder, A., Arndt, K., Das, S.
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<strong>The first case of CDK5RAP2-related primary microcephaly in a non-consanguineous patient identified by next generation sequencing.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23726037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23726037</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23726037" 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.braindev.2013.05.001" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 02/27/2018
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 10/06/2016<br>Patricia A. Hartz - updated : 03/31/2016<br>Cassandra L. Kniffin - updated : 4/30/2014<br>Cassandra L. Kniffin - updated : 12/17/2013<br>Ada Hamosh - updated : 10/24/2013<br>Patricia A. Hartz - updated : 7/31/2007<br>Victor A. McKusick - updated : 3/29/2005
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz : 10/24/2003
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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 : 03/08/2018
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<span class="mim-text-font">
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carol : 03/07/2018<br>ckniffin : 02/27/2018<br>mgross : 10/06/2016<br>mgross : 03/31/2016<br>mcolton : 8/12/2015<br>carol : 5/1/2014<br>mcolton : 5/1/2014<br>ckniffin : 4/30/2014<br>carol : 12/18/2013<br>carol : 12/18/2013<br>ckniffin : 12/17/2013<br>alopez : 10/24/2013<br>wwang : 6/2/2011<br>mgross : 10/3/2007<br>terry : 7/31/2007<br>alopez : 5/10/2005<br>tkritzer : 4/1/2005<br>terry : 3/29/2005<br>mgross : 10/24/2003
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<span class="mim-font">
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<strong>*</strong> 608201
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</h3>
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<h3>
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<span class="mim-font">
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CDK5 REGULATORY SUBUNIT-ASSOCIATED PROTEIN 2; CDK5RAP2
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</h3>
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</div>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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CENTROSOMAL PROTEIN, 215-KD; CEP215<br />
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KIAA1633
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</h4>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: CDK5RAP2</em></strong>
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<strong>
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<em>
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Cytogenetic location: 9q33.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 9:120,388,875-120,580,167 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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Location
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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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Inheritance
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<th>
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Phenotype <br /> mapping key
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<tbody>
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<span class="mim-font">
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9q33.2
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<td>
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<span class="mim-font">
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Microcephaly 3, primary, autosomal recessive
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</td>
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<td>
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<span class="mim-font">
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604804
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<td>
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<span class="mim-font">
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Autosomal recessive
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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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</td>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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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 CDK5RAP2 gene encodes a centrosomal protein that localizes to the spindle poles during mitosis (summary by Hassan et al., 2007 and Lizarraga et al., 2010). </p>
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</span>
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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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<span class="mim-text-font">
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<p>By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned CDK5RAP2, which they designated KIAA1633. The deduced protein contains 1,561 amino acids. RT-PCR ELISA detected moderate to high expression of CDK5RAP2 in all tissues and specific brain regions examined. Highest levels were detected in skeletal muscle, fetal liver, brain, kidney, and ovary. Within specific brain regions, highest expression was detected in thalamus, corpus callosum, substantia nigra, hippocampus, and caudate nucleus. </p><p>Using NCK5A (CDK5R1; 603460) as bait in a yeast 2-hybrid screen of a brain cDNA library, Ching et al. (2000) obtained a partial clone of CDK5RAP2, which they designated C48. Northern blot analysis detected expression in all tissues examined, with highest levels in heart and skeletal muscle. Ching et al. (2000) also cloned full-length rat Cdk5rap2 from a brain cDNA library. The deduced 217-amino acid rat protein has a serine-rich N terminus and shares a region of homology with restin (179838), an intermediate filament-associated protein. </p><p>Evans et al. (2006) stated that the CDK5RAP2 protein contains 2 structural maintenance of chromosomes (SMC; see 608685) domains. </p><p>Graser et al. (2007) reported that CEP215 encodes 2 isoforms containing 1,893 and 1,814 amino acids. Both isoforms have an N-terminal microtubule-association domain and 10 coiled-coil domains. Compared with the long isoform, the short isoform has a deletion near the C terminus that involves part of coiled-coil domain-9. Immunohistochemical and immunoelectron microscopic analyses of U2OS cells showed CEP215 at centriolar cylinders. CEP215 staining persisted on centrosomes throughout the cell cycle. Western blot analysis of HeLa, U2OS, and 293T cells detected CEP215 at an apparent molecular mass of approximately 210 kD. </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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<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>Bond et al. (2005) stated that the CDK5RAP2 gene contains 34 exons. Evans et al. (2006) determined that the CDK5RAP2 gene contains 38 exons and spans 190 kb. </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>Graser et al. (2007) stated that the CDK5RAP2 gene maps to chromosome 9q33.2. </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>Ching et al. (2000) determined that rat Cdk5rap2 was phosphorylated by Cdk5 kinase (123831). </p><p>Using a small interfering RNA screen, Graser et al. (2007) found that depletion of CNAP1 (CEP2; 609689), rootletin (CROCC; 615776), pericentrin (PCNT; 605925), CEP68 (616889), or CEP215 reduced centrosome cohesion and caused centrosome splitting in U2OS, A549, and RPE1 cells. Depletion of CNAP1 and rootletin produced the most severe phenotype. Depletion of pericentrin caused loss of CEP215 from centrioles, but depletion of CEP215 had no effect on pericentrin. Graser et al. (2007) concluded that CEP215 and pericentrin functionally interact and influence centrosome cohesion through an indirect mechanism independent of CNAP1, rootletin, and CEP68. </p><p>Lancaster et al. (2013) developed a human pluripotent stem cell-derived 3-dimensional organoid culture system, termed cerebral organoids, that develop various discrete, although interdependent, brain regions. These included a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids recapitulated features of human cortical development, namely, characteristic progenitor zone organization with abundant outer radial glial stem cells. Lancaster et al. (2013) used RNA interference and patient-specific induced pluripotent stem cells to model microcephaly caused by deficiency of CDK5RAP2 (MCPH3; 604804), a disorder that has been difficult to recapitulate in mice. Lancaster et al. (2013) demonstrated premature neuronal differentiation in patient organoids, a defect that could help to explain the disease phenotype. </p><p>Using a proximity interaction assay with U2OS cells, Firat-Karalar et al. (2014) found that full-length CEP152 (613529) interacted with CDK5RAP2. Coimmunoprecipitation analysis in HEK293T cells confirmed direct interaction between CEP152 and CDK5RAP2. Depletion of CEP152 reduced centrosome localization of CDK5RAP2. </p>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In a Pakistani family with autosomal recessive primary microcephaly-3 (MCPH3; 604804), Moynihan et al. (2000) mapped the disorder to chromosome 9q34 by autozygosity mapping. Bond et al. (2005) used a positional cloning strategy to identify genes in this region in 2 families, including the one previously described by Moynihan et al. (2000). Genotyping polymorphic microsatellite markers in the 2 families narrowed the region to 2.2 Mb. Bioinformatic analysis of the region identified CDK5RAP2 as a likely candidate. A homozygous mutation in the CDK5RAP2 gene was identified in affected members of each of the 2 families (608201.0001-608201.0002, respectively). Each mutation was absent from 380 northern Pakistani control chromosomes, showed the expected disease segregation in families, and was not present in chimpanzee, gorilla, orangutan, gibbon, mouse, or rat. </p><p>In a 6-year-old girl, born of consanguineous Somali parents, with MCPH3, Pagnamenta et al. (2012) identified a homozygous truncating mutation in the CDK5RAP2 gene (E234X; 608201.0003). </p><p>In a patient with MCPH3 and a simplified gyral pattern on brain imaging, Lancaster et al. (2013) identified compound heterozygous truncating mutations in the CDK5RAP2 gene (608201.0004 and 608201.0005). </p><p>In a 6-year-old girl of Caucasian and Cherokee ancestry with MCPH3 and normal brain imaging, Tan et al. (2014) identified compound heterozygous mutations in the CDK5RAP2 gene (608201.0006 and 608201.0007). The mutations were found by next-generation sequencing of targeted microcephaly genes. The girl was 1 of triplets; the other 2 sisters were unaffected. </p><p>In an 11-year-old boy with MCPH3, Pagnamenta et al. (2016) identified compound heterozygous mutations in the CDK5RAP2 gene (608201.0008 and 608201.0009). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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In 3 adult sibs, born of unrelated French Canadian parents, with isolated agenesis of the corpus callosum (see 217990), Jouan et al. (2016) identified compound heterozygous missense variants in the CDK5RAP2 gene (NM_018249.5): a c.280G-C transversion, resulting in a gly94-to-arg (G94R) substitution, and a c.3695A-G transition, resulting in an asn1232-to-ser (N1232S) substitution. The variants, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both variants affected highly conserved nucleotides. G94R was found in 2 of 288 unaffected controls, but neither homozygous nor compound heterozygous variants were found. Both variants were present at low frequencies in the ExAC database (G94R at 8.237 x 10(-6), N1232S at 8.238 x 10(-6)), but were not found in the dbSNP (build 132), 1000 Genomes Project, or Exome Variant Server databases. Lymphoblastoid cells from 1 of the patients showed biallelic expression of the variants; functional studies of the variants were not performed. Jouan et al. (2016) suggested that hypomorphic CDK5RAP2 variants with residual function may predispose to agenesis of the corpus callosum, while more detrimental loss-of-function variants may result in the more severe phenotype of microcephaly. </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The mouse Hertwig's anemia (an) mutant shows peripheral blood cytopenias, spontaneous aneuploidy, and a predisposition to hematopoietic tumors. Lizarraga et al. (2010) found that the 'an' mutation was a homozygous mutation in the Cdk5rap2 gene that causes a deletion of exon 4. In addition to the hematopoietic phenotype, the mutant mice showed microcephaly with hypoplasia of several brain regions, including the cortex and hippocampus. Neuronal progenitors from the mutant mice showed proliferative and survival defects: they exited the cell cycle prematurely and many underwent apoptosis. These defects were associated with impaired mitotic progression coupled with abnormal mitotic spindle pole number and mitotic orientation. These findings suggested that the reduction in brain size observed in humans with mutations in CDK5RAP2 is associated with impaired centrosomal function and with changes in mitotic spindle orientation during the proliferation of neuronal progenitors. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>9 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CDK5RAP2, TYR82TER
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<br />
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SNP: rs199422126,
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gnomAD: rs199422126,
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ClinVar: RCV000002594
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a Pakistani family with autosomal recessive primary microcephaly-3 (MCPH3; 604804) previously described by Moynihan et al. (2000), Bond et al. (2005) identified a homozygous 243T-A transversion in exon 4 of the CDK5RAP2 gene, resulting in a ser81-to-ter (S81X) substitution. </p><p>In 4 sibs, born of consanguineous Pakistani parents of Kashmiri origin, with MCPH3, Hassan et al. (2007) identified a homozygous c.246T-A transversion in the CDK5RAP2 gene, resulting in a tyr82-to-ter (Y82X) substitution. The patients had a head circumference of -4 to -7 SD and mental retardation. The mutation was found by homozygosity mapping and candidate gene analysis, segregated with the disorder in the family, and was not present in 200 control chromosomes. Hassan et al. (2007) stated that this was the same mutation as that reported by Bond et al. (2005), and postulated a founder effect. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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CDK5RAP2, IVS26AS, A-G, -15
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<br />
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|
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SNP: rs387906274,
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gnomAD: rs387906274,
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ClinVar: RCV000002595
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a Pakistani family with autosomal recessive primary microcephaly-3 (MCPH3; 604804), Bond et al. (2005) identified a homozygous A-to-G transition at position -15 of intron 26 of the CDK5RAP2 gene, resulting in a new splice acceptor site with the addition of 4 new amino acids and a premature stop codon. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0003 MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
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</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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CDK5RAP2, GLU234TER
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<br />
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SNP: rs398122971,
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ClinVar: RCV000076922
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 6-year-old girl, born of consanguineous Somali parents, with autosomal recessive primary microcephaly-3 (MCPH3; 604804), Pagnamenta et al. (2012) identified a homozygous c.700G-T transversion in exon 8 of the CDK5RAP2 gene, resulting in a glu234-to-ter (E234X) substitution. The mutation was not found in over 5,000 Caucasian and African American samples in the Exome Variant Server database. The patient had delayed psychomotor development, microcephaly (-8.9 SD), and mild muscular hypotonia. She was diagnosed at age 3 years 10 months with moderate to severe sensorineural hearing loss, which may have been due to another genetic defect given the consanguinity in the family. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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CDK5RAP2, GLU1516TER
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<br />
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|
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SNP: rs374351172,
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|
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|
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gnomAD: rs374351172,
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|
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|
|
|
ClinVar: RCV000076923, RCV001311021, RCV003398664
|
|
|
|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with autosomal recessive primary microcephaly-3 (MCPH3; 604804), Lancaster et al. (2013) identified compound heterozygous mutations in the CDK5RAP2 gene: a c.4546G-T transversion resulting in a glu1516-to-ter (E1516X) substitution, and a c.4672C-T transition resulting in an arg1558-to-ter (R1558X; 608201.0005) substitution. Each unaffected parent was heterozygous for 1 of the mutations. CDK5RAP2 protein was undetectable in patient cell lysates. The patient had severe microcephaly (-13.2 SD), short stature (-6.7 SD), simplified gyral pattern on brain imaging, delayed psychomotor development, and mixed conductive/sensorineural hearing loss. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
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CDK5RAP2, ARG1558TER
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<br />
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|
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SNP: rs373278668,
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|
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|
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gnomAD: rs373278668,
|
|
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|
|
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ClinVar: RCV000076924
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the arg1558-to-ter (R1558X) mutation in the CDK5RAP2 gene that was found in compound heterozygous state in a patient with autosomal recessive primary microcephaly-3 (MCPH3; 604804) by Lancaster et al. (2013), see 608201.0004. </p>
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CDK5RAP2, 5-BP DEL, NT524
|
|
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|
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<br />
|
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|
|
SNP: rs587783393,
|
|
|
|
|
|
gnomAD: rs587783393,
|
|
|
|
|
|
ClinVar: RCV000115025, RCV002515791
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 6-year-old girl with autosomal recessive primary microcephaly-3 (MCPH3; 604804), Tan et al. (2014) identified compound heterozygous mutations in the CDK5RAP2 gene: a 5-bp deletion (c.524_528del) in exon 7, resulting in a frameshift and premature termination (Gln175ArgfsTer42), and a G-to-A transition in intron 26 (c.4005-1G-A; 608201.0007), predicted to result in a splicing defect. Each unaffected parent was heterozygous for 1 of the mutations, which were found by next-generation sequencing of targeted microcephaly genes and confirmed by Sanger sequencing. The mother of the patient was of northern European descent and the father was Caucasian with Cherokee ancestry. The girl was 1 of triplets; the other 2 sisters were unaffected. The patient had severe microcephaly (-8.9 SD) and developmental delay, but brain MRI showed no structural abnormalities. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CDK5RAP2, IVS26AS, G-A, -1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587783387,
|
|
|
|
|
|
gnomAD: rs587783387,
|
|
|
|
|
|
ClinVar: RCV000145479, RCV003556186
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the splice site mutation in the CDK5RAP2 gene (c.4005-1G-A) that was found in compound heterozygous state in a patient with autosomal recessive primary microcephaly-3 (MCPH3; 604804) by Tan et al. (2014), see 608201.0006. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CDK5RAP2, IVS30DS, G-C, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs869025200,
|
|
|
|
|
|
|
|
ClinVar: RCV000207398
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 11-year-old boy (patient BRC081), born of unrelated Caucasian parents, with autosomal recessive primary microcephaly-3 (MCPH3; 604804), Pagnamenta et al. (2016) identified compound heterozygous mutations in the CDK5RAP2 gene: a G-to-C transversion (c.4604+1G-C, NM_018249.5) in exon 30, predicted to alter a splice site, and a 1-bp deletion (c.3097delG; 608201.0009) in exon 23, predicted to result in a frameshift and premature termination (Val1033fsTer41). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the ExAC database. Analysis of patient cells showed that c.4604+1G-C mutation resulted in alternative use of a cryptic exonic splice donor site, which would result in premature termination (Val1526fsTer15). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CDK5RAP2, 1-BP DEL, 3097G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs747831095,
|
|
|
|
|
|
gnomAD: rs747831095,
|
|
|
|
|
|
ClinVar: RCV000207363, RCV002517035, RCV003556239
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 1-bp deletion (c.3097delG, NM_018249.5) in the CDK5RAP2 gene, predicted to result in a frameshift and premature termination (Val1033fsTer41), that was found in compound heterozygous state in a patient with autosomal recessive primary microcephaly-3 (MCPH3; 604804) by Pagnamenta et al. (2016), see 608201.0008. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
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|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bond, J., Roberts, E., Springell, K., Lizarraga, S., Scott, S., Higgins, J., Hampshire, D. J., Morrison, E. E., Leal, G. F., Silva, E. O., Costa, S. M. R., Baralle, D., Raponi, M., Karbani, G., Rashid, Y., Jafri, H., Bennett, C., Corry, P., Walsh, C. A., Woods, C. G.
|
|
<strong>A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size.</strong>
|
|
Nature Genet. 37: 353-355, 2005. Note: Erratum: Nature Genet. 37: 555 only, 2005.
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|
|
|
|
|
[PubMed: 15793586]
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|
|
[Full Text: https://doi.org/10.1038/ng1539]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Ching, Y. P., Qi, Z., Wang, J. H.
|
|
<strong>Cloning of three novel neuronal Cdk5 activator binding proteins.</strong>
|
|
Gene 242: 285-294, 2000.
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|
|
[PubMed: 10721722]
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[Full Text: https://doi.org/10.1016/s0378-1119(99)00499-0]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Evans, P. D., Vallender, E. J., Lahn, B. T.
|
|
<strong>Molecular evolution of the brain size regulator genes CDK5RAP2 and CENPJ.</strong>
|
|
Gene 375: 75-79, 2006.
|
|
|
|
|
|
[PubMed: 16631324]
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|
|
[Full Text: https://doi.org/10.1016/j.gene.2006.02.019]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Firat-Karalar, E., Rauniyar, N., Yates, J. R., III, Stearns, T.
|
|
<strong>Proximity interactions among centrosome components identify regulators of centriole duplication.</strong>
|
|
Curr. Biol. 24: 664-670, 2014.
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|
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|
|
[PubMed: 24613305]
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|
[Full Text: https://doi.org/10.1016/j.cub.2014.01.067]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Graser, S., Stierhof, Y.-D., Nigg, E. A.
|
|
<strong>Cep68 and Cep215 (Cdk5rap2) are required for centrosome cohesion.</strong>
|
|
J. Cell. Sci. 120: 4321-4331, 2007.
|
|
|
|
|
|
[PubMed: 18042621]
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|
|
[Full Text: https://doi.org/10.1242/jcs.020248]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Hassan, M. J., Khurshid, M., Azeem, Z., John, P., Ali, G., Chishti, M. S., Ahmad, W.
|
|
<strong>Previously described sequence variant in CDK5RAP2 gene in a Pakistani family with autosomal recessive primary microcephaly.</strong>
|
|
BMC Med. Genet. 8: 58, 2007. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: 17764569]
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|
|
|
|
|
[Full Text: https://doi.org/10.1186/1471-2350-8-58]
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|
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Jouan, L., Ouled Amar Bencheikh, B., Daoud, H., Dionne-Laporte, A., Dobrzeniecka, S., Spiegelman, D., Rochefort, D., Hince, P., Szuto, A., Lassonde, M., Barbelanne, M., Tsang, W. Y., Dion, P. A., Theoret, H., Rouleau, G. A.
|
|
<strong>Exome sequencing identifies recessive CDK5RAP2 variants in patients with isolated agenesis of corpus callosum.</strong>
|
|
Europ. J. Hum. Genet. 24: 607-610, 2016.
|
|
|
|
|
|
[PubMed: 26197979]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ejhg.2015.156]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., Homfray, T., Penninger, J. M., Jackson, A. P., Knoblich, J. A.
|
|
<strong>Cerebral organoids model human brain development and microcephaly.</strong>
|
|
Nature 501: 373-379, 2013.
|
|
|
|
|
|
[PubMed: 23995685]
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|
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|
|
[Full Text: https://doi.org/10.1038/nature12517]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Lizarraga, S. B., Margossian, S. P., Harris, M. H., Campagna, D. R., Han, A.-P., Blevins, S., Mudbhary, R., Barker, J. E., Walsh, C. A., Fleming, M. D.
|
|
<strong>Cdk5rap2 regulates centrosome function and chromosome segregation in neuronal progenitors.</strong>
|
|
Development 137: 1907-1917, 2010.
|
|
|
|
|
|
[PubMed: 20460369]
|
|
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|
|
[Full Text: https://doi.org/10.1242/dev.040410]
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Moynihan, L., Jackson, A. P., Roberts, E., Karbani, G., Lewis, I., Corry, P., Turner, G., Mueller, R. F., Lench, N. J., Woods, C. G.
|
|
<strong>A third novel locus for primary autosomal recessive microcephaly maps to chromosome 9q34.</strong>
|
|
Am. J. Hum. Genet. 66: 724-727, 2000.
|
|
|
|
|
|
[PubMed: 10677332]
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|
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|
|
[Full Text: https://doi.org/10.1086/302777]
|
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</p>
|
|
</li>
|
|
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<li>
|
|
<p class="mim-text-font">
|
|
Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O.
|
|
<strong>Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.</strong>
|
|
DNA Res. 7: 273-281, 2000.
|
|
|
|
|
|
[PubMed: 10997877]
|
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|
|
[Full Text: https://doi.org/10.1093/dnares/7.4.271]
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Pagnamenta, A. T., Howard, M. F., Knight, S. J. L., Keays, D. A., Quaghebeur, G., Taylor, J. C., Kini,, U.
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<strong>Activation of an exonic splice-donor site in exon 30 of CDK5RAP2 in a patient with severe microcephaly and pigmentary abnormalities.</strong>
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Clin. Case Rep. 4: 952-956, 2016.
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[PubMed: 27761245]
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[Full Text: https://doi.org/10.1002/ccr3.663]
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Pagnamenta, A. T., Murray, J. E., Yoon, G., Sadighi Akha, E., Harrison, V., Bicknell, L. S., Ajilogba, K., Stewart, H., Kini, U., Taylor, J. C., Keays, D. A., Jackson, A. P., Knight, S. J. L.
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<strong>A novel nonsense CDK5RAP2 mutation in a Somali child with primary microcephaly and sensorineural hearing loss.</strong>
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Am. J. Med. Genet. 158A: 2577-2582, 2012.
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[PubMed: 22887808]
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[Full Text: https://doi.org/10.1002/ajmg.a.35558]
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Tan, C. A., Topper, S., Melver, C. W., Stein, J., Reeder, A., Arndt, K., Das, S.
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<strong>The first case of CDK5RAP2-related primary microcephaly in a non-consanguineous patient identified by next generation sequencing.</strong>
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Brain Dev. 36: 351-355, 2014.
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[PubMed: 23726037]
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[Full Text: https://doi.org/10.1016/j.braindev.2013.05.001]
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Cassandra L. Kniffin - updated : 02/27/2018<br>Patricia A. Hartz - updated : 10/06/2016<br>Patricia A. Hartz - updated : 03/31/2016<br>Cassandra L. Kniffin - updated : 4/30/2014<br>Cassandra L. Kniffin - updated : 12/17/2013<br>Ada Hamosh - updated : 10/24/2013<br>Patricia A. Hartz - updated : 7/31/2007<br>Victor A. McKusick - updated : 3/29/2005
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Patricia A. Hartz : 10/24/2003
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