4095 lines
387 KiB
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Entry
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- *600855 - DUAL-SPECIFICITY TYROSINE PHOSPHORYLATION-REGULATED KINASE 1A; DYRK1A
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600855</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<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>
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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="#cytogenetics">Cytogenetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#evolution">Evolution</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#otherFeatures">Other Features</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600855">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000157540;t=ENST00000647188" 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=1859" 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=600855" 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=ENSG00000157540;t=ENST00000647188" 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_001347721,NM_001347722,NM_001347723,NM_001396,NM_101395,NM_130436,NM_130438" 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_001347721" 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=600855" 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=09018&isoform_id=09018_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/DYRK1A" 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/405725,1381156,1526446,1663726,1772438,2969909,2969911,3219996,3790366,3790368,3790370,4868113,18765750,18765752,18765756,18765758,119630107,119630108,119630109,119630110,119630111,119630112,119630113,194377702,485043279,485043281,1113820491,1113820493,1113820495" 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/Q13627" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=1859" 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=ENSG00000157540;t=ENST00000647188" 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=DYRK1A" 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=DYRK1A" 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+1859" 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/DYRK1A" 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:1859" 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/1859" 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=chr21&hgg_gene=ENST00000647188.2&hgg_start=37365573&hgg_end=37526358&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:3091" 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:3091" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/dyrk1a" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600855[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=600855[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/DYRK1A/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/ENSG00000157540" 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=DYRK1A" 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=DYRK1A" 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=DYRK1A" 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=DYRK1A&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/PA27545" 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:3091" 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/FBgn0259168.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:1330299" 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/DYRK1A#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:1330299" 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/1859/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=1859" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00003149;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-050302-29" 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=DYRK1A&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1179301003<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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600855
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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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DUAL-SPECIFICITY TYROSINE PHOSPHORYLATION-REGULATED KINASE 1A; DYRK1A
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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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
DUAL-SPECIFICITY TYROSINE PHOSPHORYLATION-REGULATED KINASE 1; DYRK1<br />
|
|
DUAL-SPECIFICITY TYROSINE PHOSPHORYLATION-REGULATED KINASE; DYRK<br />
|
|
MNB PROTEIN KINASE, SERINE/THREONINE-SPECIFIC<br />
|
|
MINIBRAIN, DROSOPHILA, HOMOLOG OF; MNB; MNBH
|
|
</span>
|
|
</h4>
|
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</div>
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=DYRK1A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">DYRK1A</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/21/100?start=-3&limit=10&highlight=100">21q22.13</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr21:37365573-37526358&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'})">21:37,365,573-37,526,358</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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</span>
|
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</p>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
</th>
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<th>
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|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/21/100?start=-3&limit=10&highlight=100">
|
|
21q22.13
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Intellectual developmental disorder, autosomal dominant 7
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/614104"> 614104 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
</span>
|
|
</td>
|
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</tr>
|
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<p>The DYRK1A gene encodes a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family and participates in various cellular processes. It is a highly conserved gene located in the so-called Down Syndrome critical region (DSCR), a part of chromosome 21 that is responsible for the majority of phenotypic features in Down syndrome (<a href="/entry/190685">190685</a>) (summary by <a href="#29" class="mim-tip-reference" title="van Bon, B. W. M., Hoischen, A., Hehir-Kwa, J., de Brouwer, A. P. M., Ruivenkamp, C., Gijsbers, A. C. J., Marcelis, C. L., de Leeuw, N., Veltman, J. A., Brunner, H. G., de Vries, B. B. A. <strong>Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly.</strong> Clin. Genet. 79: 296-299, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21294719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21294719</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2010.01544.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21294719">van Bon et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21294719" 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 the course of cloning transcripts from the region of human chromosome 21 that is homologous to the region of mouse chromosome 16 containing the 'weaver' (wv) locus (see <a href="/entry/600877">600877</a>), <a href="#21" class="mim-tip-reference" title="Patil, N., Cox, D. R., Bhat, D., Faham, M., Myers, R. M., Peterson, A. S. <strong>A potassium channel mutation in weaver mice implicates membrane excitability in granule cell differentiation.</strong> Nature Genet. 11: 126-129, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550338</a>] [<a href="https://doi.org/10.1038/ng1095-126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550338">Patil et al. (1995)</a> identified a gene that encodes a serine/threonine-specific protein kinase. The closest relative of this kinase was found to be the Drosophila 'minibrain' gene (mnb) (<a href="#28" class="mim-tip-reference" title="Tejedor, F., Zhu, X. R., Kaltenbach, E., Ackermann, A., Baumann, A., Canal, I., Heisenberg, M., Fischbach, K. F., Pongs, O. <strong>Minibrain: a new protein kinase family involved in postembryonic neurogenesis in Drosophila.</strong> Neuron 14: 287-301, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7857639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7857639</a>] [<a href="https://doi.org/10.1016/0896-6273(95)90286-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7857639">Tejedor et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7550338+7857639" 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="#24" class="mim-tip-reference" title="Shindoh, N., Kudoh, J., Maeda, H., Yamaki, A., Minoshima, S., Shimizu, Y., Shimizu, N. <strong>Cloning of a human homolog of the Drosophila minibrain/rat Dyrk gene from 'the Down syndrome critical region' of chromosome 21.</strong> Biochem. Biophys. Res. Commun. 225: 92-99, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8769099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8769099</a>] [<a href="https://doi.org/10.1006/bbrc.1996.1135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8769099">Shindoh et al. (1996)</a> performed exon trapping to find exons within YAC clones spanning the 2-Mb Down syndrome critical region of human chromosome 21. Of more than 160 exons isolated, they found 6 that had significant identity at the amino acid level to the Drosophila 'minibrain' gene. Using 1 of these exons as a probe, they cloned the full-length human cDNA from a human fetal brain cDNA library. Sequence analysis of this cDNA revealed an open reading frame encoding a polypeptide of 754 amino acids. <a href="#24" class="mim-tip-reference" title="Shindoh, N., Kudoh, J., Maeda, H., Yamaki, A., Minoshima, S., Shimizu, Y., Shimizu, N. <strong>Cloning of a human homolog of the Drosophila minibrain/rat Dyrk gene from 'the Down syndrome critical region' of chromosome 21.</strong> Biochem. Biophys. Res. Commun. 225: 92-99, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8769099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8769099</a>] [<a href="https://doi.org/10.1006/bbrc.1996.1135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8769099">Shindoh et al. (1996)</a> stated that this gene, termed MNB by them, represents the human homolog of the Drosophila mnb gene and of the rat Dyrk gene. The rat Dyrk gene differs from it by only 4 amino acids. Northern blot analysis of MNB revealed 2 transcripts of 6.0 and 7.5 kb. The 6.0-kb transcript was found to be present in all tissues examined, with highest levels of expression in skeletal muscle, testis, fetal lung, and fetal kidney. The 7.5-kb transcript was found to be expressed at a relatively lower level and was found only in adult heart, placenta, spleen, and testis. <a href="#24" class="mim-tip-reference" title="Shindoh, N., Kudoh, J., Maeda, H., Yamaki, A., Minoshima, S., Shimizu, Y., Shimizu, N. <strong>Cloning of a human homolog of the Drosophila minibrain/rat Dyrk gene from 'the Down syndrome critical region' of chromosome 21.</strong> Biochem. Biophys. Res. Commun. 225: 92-99, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8769099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8769099</a>] [<a href="https://doi.org/10.1006/bbrc.1996.1135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8769099">Shindoh et al. (1996)</a> concluded that the human MNB protein may play a significant role in a signaling pathway regulating cell proliferation and may be involved in normal brain development and in the pathogenesis of Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8769099" 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="#27" class="mim-tip-reference" title="Song, W.-J., Sternberg, L. R., Kasten-Sportes, C., Van Keuren, M. L., Chung, S.-H., Slack, A. C., Miller, D. E., Glover, T. W., Chiang, P.-W., Lou, L., Kurnit, D. M. <strong>Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome 'critical region.'</strong> Genomics 38: 331-339, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8975710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8975710</a>] [<a href="https://doi.org/10.1006/geno.1996.0636" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8975710">Song et al. (1996)</a> cloned the DYRK gene and its murine counterpart (Dyrk) and compared it to the rat Dyrk gene. The 3 mammalian genes are highly conserved, being more than 99% identical at the protein level over their 763-amino acid open reading frame; in addition, the mammalian genes are 83% identical over 414 amino acids to the smaller 542-amino acid mnb protein of Drosophila. The predicted human and murine proteins both contain a nuclear targeting signal sequence, a protein kinase domain, a putative leucine zipper motif, and a highly conservative 13-consecutive-histidine repeat. Northern blot analysis indicated that both human and murine genes encode approximately 6-kb transcripts. PCR screening of cDNA libraries derived from various human and murine tissues indicated that DYRK and Dyrk are expressed both during development and in the adult. In situ hybridization of Dyrk to mouse embryos (days 13, 15, and 17 postcoitus) indicated a differential spatial and temporal pattern of expression, with the most abundant signal localized in brain matter, spinal cord, and retina. The observed expression pattern was coincident with many of the clinical findings in trisomy 21. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8975710" 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="#26" class="mim-tip-reference" title="Song, W.-J., Chung, S.-H., Kurnit, D. M. <strong>The murine Dyrk protein maps to chromosome 16, localizes to the nucleus, and can form multimers.</strong> Biochem. Biophys. Res. Commun. 231: 640-644, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9070862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9070862</a>] [<a href="https://doi.org/10.1006/bbrc.1997.6154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9070862">Song et al. (1997)</a> found that mouse Dyrk is expressed in frontal brain nuclei during mouse embryogenesis and that it interacts with other proteins. The chromosomal locus of DYRK, its homology to the mnb gene, and the in situ hybridization expression patterns of murine Dyrk, combined with the fact that transgenic mice for a YAC to which Dyrk maps are mentally deficient, suggested to <a href="#27" class="mim-tip-reference" title="Song, W.-J., Sternberg, L. R., Kasten-Sportes, C., Van Keuren, M. L., Chung, S.-H., Slack, A. C., Miller, D. E., Glover, T. W., Chiang, P.-W., Lou, L., Kurnit, D. M. <strong>Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome 'critical region.'</strong> Genomics 38: 331-339, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8975710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8975710</a>] [<a href="https://doi.org/10.1006/geno.1996.0636" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8975710">Song et al. (1996)</a> that DYRK may be involved in the abnormal neurogenesis found in Down syndrome. They considered DYRK a good candidate to mediate some of the pleiotropic effects of Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9070862+8975710" 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="Chen, H., Antonarakis, S. E. <strong>Localisation of a human homologue of the Drosophila mnb and rat Dyrk genes to chromosome 21q22.2.</strong> Hum. Genet. 99: 262-265, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9048932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9048932</a>] [<a href="https://doi.org/10.1007/s004390050350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9048932">Chen and Antonarakis (1997)</a> used exon trapping to identify human chromosome 21-encoded genes and identified in this way the homolog of the Drosophila mnb gene. By Northern analysis they found high expression levels of a 6.8-kb RNA transcript in adult heart, brain, placenta, and skeletal muscle, and in fetal lung, liver, and kidney. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9048932" 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 combination of cDNA library screening and RACE, <a href="#9" class="mim-tip-reference" title="Guimera, J., Casas, C., Estivill, X., Pritchard, M. <strong>Human minibrain homologue (MNBH/DYRK1): characterization, alternative splicing, differential tissue expression, and overexpression in Down syndrome.</strong> Genomics 57: 407-418, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10329007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10329007</a>] [<a href="https://doi.org/10.1006/geno.1999.5775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10329007">Guimera et al. (1999)</a> identified 2 transcription start sites, resulting in MNBHa and MNBHb transcripts. Northern blot analysis of multiple tissues using a probe specific to MNBHa revealed ubiquitous expression, while a probe specific to MNBHb revealed expression only in heart and skeletal muscle. <a href="#9" class="mim-tip-reference" title="Guimera, J., Casas, C., Estivill, X., Pritchard, M. <strong>Human minibrain homologue (MNBH/DYRK1): characterization, alternative splicing, differential tissue expression, and overexpression in Down syndrome.</strong> Genomics 57: 407-418, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10329007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10329007</a>] [<a href="https://doi.org/10.1006/geno.1999.5775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10329007">Guimera et al. (1999)</a> also identified at least 4 protein isoforms arising from alternative splicing of the C terminus. All isoforms contain a PEST sequence, which potentially directs rapid degradation of the protein. The most abundant transcript in brain produces the largest isoform (isoform-1), a 763-amino acid protein with a calculated molecular mass of about 85.6 kD. This isoform also contains a histidine repeat and a serine/threonine domain not found in the other isoforms. <a href="#9" class="mim-tip-reference" title="Guimera, J., Casas, C., Estivill, X., Pritchard, M. <strong>Human minibrain homologue (MNBH/DYRK1): characterization, alternative splicing, differential tissue expression, and overexpression in Down syndrome.</strong> Genomics 57: 407-418, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10329007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10329007</a>] [<a href="https://doi.org/10.1006/geno.1999.5775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10329007">Guimera et al. (1999)</a> determined that the MNBH variant reported by <a href="#24" class="mim-tip-reference" title="Shindoh, N., Kudoh, J., Maeda, H., Yamaki, A., Minoshima, S., Shimizu, Y., Shimizu, N. <strong>Cloning of a human homolog of the Drosophila minibrain/rat Dyrk gene from 'the Down syndrome critical region' of chromosome 21.</strong> Biochem. Biophys. Res. Commun. 225: 92-99, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8769099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8769099</a>] [<a href="https://doi.org/10.1006/bbrc.1996.1135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8769099">Shindoh et al. (1996)</a> is 9 amino acids shorter than isoform-1 near the N terminus and results from the use of an alternative splice acceptor site. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10329007+8769099" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Lee, S. B., Frattini, V., Bansal, M., Castano, A. M., Sherman, D., Hutchinson, K., Bruce, J. N., Califano, A., Liu, G., Cardozo, T., Iavarone, A., Lasorella, A. <strong>An ID2-dependent mechanism for VHL inactivation in cancer.</strong> Nature 529: 172-177, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26735018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26735018</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26735018[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/nature16475" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26735018">Lee et al. (2016)</a> reported that DYRK1A and DYRK1B (<a href="/entry/604556">604556</a>) kinases phosphorylate ID2 (<a href="/entry/600386">600386</a>) on threonine-27 (thr27). Hypoxia downregulates this phosphorylation via inactivation of DYRK1A and DYRK1B. The activity of these kinases is stimulated in normoxia by the oxygen-sensing prolyl hydroxylase PHD1 (EGLN2; <a href="/entry/606424">606424</a>). ID2 binds to the VHL (<a href="/entry/608537">608537</a>) ubiquitin ligase complex, displaces VHL-associated cullin-2 (<a href="/entry/603135">603135</a>), and impairs HIF2-alpha (<a href="/entry/603349">603349</a>) ubiquitylation and degradation. Phosphorylation of thr27 of ID2 by DYRK1 blocks ID2-VHL interaction and preserves HIF2-alpha ubiquitylation. In glioblastoma, ID2 positively modulates HIF2-alpha activity. Conversely, elevated expression of DYRK1 phosphorylates thr27 of ID2, leading to HIF2-alpha destabilization, loss of glioma stemness, inhibition of tumor growth, and a more favorable outcome for patients with glioblastoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26735018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Guimera, J., Casas, C., Estivill, X., Pritchard, M. <strong>Human minibrain homologue (MNBH/DYRK1): characterization, alternative splicing, differential tissue expression, and overexpression in Down syndrome.</strong> Genomics 57: 407-418, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10329007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10329007</a>] [<a href="https://doi.org/10.1006/geno.1999.5775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10329007">Guimera et al. (1999)</a> determined that the MNBH gene contains 17 alternatively spliced exons and spans 150 kb. The 5-prime untranslated region contains 2 separate promoters. One promoter, utilized by the MNBHa variant, contains a GC-rich element and no canonic TATA or CAAT boxes. The other, utilized by MNBHb, contains a CAAT box and a nonconsensus AT-rich motif. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10329007" 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>Using fluorescence in situ hybridization and regional mapping data, <a href="#27" class="mim-tip-reference" title="Song, W.-J., Sternberg, L. R., Kasten-Sportes, C., Van Keuren, M. L., Chung, S.-H., Slack, A. C., Miller, D. E., Glover, T. W., Chiang, P.-W., Lou, L., Kurnit, D. M. <strong>Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome 'critical region.'</strong> Genomics 38: 331-339, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8975710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8975710</a>] [<a href="https://doi.org/10.1006/geno.1996.0636" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8975710">Song et al. (1996)</a> localized the DYRK gene between markers D21S336 and D21S337 in the 21q22.2 region. With amplification by PCR and hybridization analysis, <a href="#5" class="mim-tip-reference" title="Chen, H., Antonarakis, S. E. <strong>Localisation of a human homologue of the Drosophila mnb and rat Dyrk genes to chromosome 21q22.2.</strong> Hum. Genet. 99: 262-265, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9048932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9048932</a>] [<a href="https://doi.org/10.1007/s004390050350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9048932">Chen and Antonarakis (1997)</a> mapped the human MNB gene on YACs located on 21q22.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9048932+8975710" 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="#26" class="mim-tip-reference" title="Song, W.-J., Chung, S.-H., Kurnit, D. M. <strong>The murine Dyrk protein maps to chromosome 16, localizes to the nucleus, and can form multimers.</strong> Biochem. Biophys. Res. Commun. 231: 640-644, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9070862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9070862</a>] [<a href="https://doi.org/10.1006/bbrc.1997.6154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9070862">Song et al. (1997)</a> mapped the murine Dyrk gene to distal mouse chromosome 16, in agreement with the mapping of human DYRK to a syntenic region of chromosome 21. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9070862" 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="#12" class="mim-tip-reference" title="Kelly, P. A., Rahmani, Z. <strong>DYRK1A enhances the mitogen-activated protein kinase cascade in PC12 cells by forming a complex with Ras, B-Raf, and MEK1.</strong> Molec. Biol. Cell 16: 3562-3573, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15917294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15917294</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15917294[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/10.1091/mbc.e04-12-1085" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15917294">Kelly and Rahmani (2005)</a> found that overexpression of human DYRK1A in PC12 rat pheochromocytoma cells potentiated their neuronal differentiation in response to nerve growth factor (see NGFB; <a href="/entry/162030">162030</a>). Differentiation required upregulation of the Ras (HRAS; <a href="/entry/190020">190020</a>)/MAP kinase (see MAPK1; <a href="/entry/176948">176948</a>) signaling pathway, but was independent of DYRK1A kinase activity. DYRK1A prolonged Erk (see MAPK3; <a href="/entry/601795">601795</a>) activation by interacting with Ras, Braf (<a href="/entry/164757">164757</a>), and Mek1 (MAP2K1; <a href="/entry/176872">176872</a>) to facilitate formation of a Ras/Braf/Mek1 multiprotein complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15917294" 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 rat hippocampal and mouse neoblastoma cell lines, <a href="#13" class="mim-tip-reference" title="Kim, E. J., Sung, J. Y., Lee, H. J., Rhim, H., Hasegawa, M., Iwatsubo, T., Min, D. S., Kim, J., Paik, S. R., Chung, K. C. <strong>Dyrk1A phosphorylates alpha-synuclein and enhances intracellular inclusion formation.</strong> J. Biol. Chem. 281: 33250-33257, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16959772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16959772</a>] [<a href="https://doi.org/10.1074/jbc.M606147200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16959772">Kim et al. (2006)</a> found that Dyrk1a interacted with alpha-synuclein (SNCA; <a href="/entry/163890">163890</a>), a component of Lewy bodies, one of the pathologic hallmarks of Parkinson disease (<a href="/entry/168600">168600</a>), Alzheimer disease (<a href="/entry/104300">104300</a>), and Lewy-body dementia (<a href="/entry/127750">127750</a>). Dyrk1a serine phosphorylated alpha-synuclein, and this phosphorylation facilitated its intracytoplasmic aggregation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16959772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Arron, J. R., Winslow, M. M., Polleri, A., Chang, C.-P., Wu, H., Gao, X., Neilson, J. R., Chen, L., Heit, J. J., Kim, S. K., Yamasaki, N., Miyakawa, T., Francke, U., Graef, I. A., Crabtree, G. R. <strong>NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21.</strong> Nature 441: 595-600, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16554754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16554754</a>] [<a href="https://doi.org/10.1038/nature04678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16554754">Arron et al. (2006)</a> reported that 2 genes, DSCR1 (RCAN1; <a href="/entry/602917">602917</a>) and DYRK1A, that lie within the Down syndrome (<a href="/entry/190685">190685</a>) critical region of human chromosome 21 act synergistically to prevent nuclear occupancy of NFATc transcription factors (see <a href="/entry/600489">600489</a>), which are regulators of vertebrate development. <a href="#2" class="mim-tip-reference" title="Arron, J. R., Winslow, M. M., Polleri, A., Chang, C.-P., Wu, H., Gao, X., Neilson, J. R., Chen, L., Heit, J. J., Kim, S. K., Yamasaki, N., Miyakawa, T., Francke, U., Graef, I. A., Crabtree, G. R. <strong>NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21.</strong> Nature 441: 595-600, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16554754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16554754</a>] [<a href="https://doi.org/10.1038/nature04678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16554754">Arron et al. (2006)</a> used mathematical modeling to predict that autoregulation within the pathway accentuates the effects of trisomy of DSCR1 and DYRK1A, leading to failure to activate NFATc target genes under specific conditions. The authors' observations of calcineurin (see <a href="/entry/114105">114105</a>)- and Nfatc-deficient mice, Dscr1- and Dyrk1a-overexpressing mice, mouse models of Down syndrome, and human trisomy 21 were consistent with these predictions. <a href="#2" class="mim-tip-reference" title="Arron, J. R., Winslow, M. M., Polleri, A., Chang, C.-P., Wu, H., Gao, X., Neilson, J. R., Chen, L., Heit, J. J., Kim, S. K., Yamasaki, N., Miyakawa, T., Francke, U., Graef, I. A., Crabtree, G. R. <strong>NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21.</strong> Nature 441: 595-600, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16554754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16554754</a>] [<a href="https://doi.org/10.1038/nature04678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16554754">Arron et al. (2006)</a> suggested that the 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down syndrome. <a href="#2" class="mim-tip-reference" title="Arron, J. R., Winslow, M. M., Polleri, A., Chang, C.-P., Wu, H., Gao, X., Neilson, J. R., Chen, L., Heit, J. J., Kim, S. K., Yamasaki, N., Miyakawa, T., Francke, U., Graef, I. A., Crabtree, G. R. <strong>NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21.</strong> Nature 441: 595-600, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16554754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16554754</a>] [<a href="https://doi.org/10.1038/nature04678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16554754">Arron et al. (2006)</a> concluded that more generally, their observations suggest that the destabilization of regulatory circuits can underlie human disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16554754" 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 resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free calcium ion levels, they are dephosphorylated by the calmodulin (<a href="/entry/114180">114180</a>)-dependent phosphatase calcineurin and translocate to the nucleus. NFAT dephosphorylation by calcineurin is countered by distinct NFAT kinases, among them casein kinase-1 (CK1; <a href="/entry/600505">600505</a>), and glycogen synthase kinase-3 (GSK3; see <a href="/entry/605004">605004</a>). <a href="#10" class="mim-tip-reference" title="Gwack, Y., Sharma, S., Nardone, J., Tanasa, B., Iuga, A., Srikanth, S., Okamura, H., Bolton, D., Feske, S., Hogan, P. G., Rao, A. <strong>A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT.</strong> Nature 441: 646-650, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16511445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16511445</a>] [<a href="https://doi.org/10.1038/nature04631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16511445">Gwack et al. (2006)</a> used a genomewide RNA interference screen in Drosophila to identify additional regulators of the signaling pathway leading from calcium ion-calcineurin to NFAT. This screen was successful because the pathways regulating NFAT subcellular localization (calcium ion influx, calcium ion-calmodulin-calcineurin signaling, and NFAT kinases) are conserved across species, even though calcium ion-regulated NFAT proteins are not themselves represented in invertebrates. Using the screen, <a href="#10" class="mim-tip-reference" title="Gwack, Y., Sharma, S., Nardone, J., Tanasa, B., Iuga, A., Srikanth, S., Okamura, H., Bolton, D., Feske, S., Hogan, P. G., Rao, A. <strong>A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT.</strong> Nature 441: 646-650, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16511445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16511445</a>] [<a href="https://doi.org/10.1038/nature04631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16511445">Gwack et al. (2006)</a> identified DYRKs as novel regulators of NFAT. DYRK1A and DYRK2 (<a href="/entry/603496">603496</a>) counter calcineurin-mediated dephosphorylation of NFAT1 by directly phosphorylating the conserved serine-proline repeat 3 (SP3) motif of the NFAT regulatory domain, thus priming further phosphorylation of the SP2 and serine-rich region 1 (SRR1) motifs by GSK3 and CK1, respectively. Thus, <a href="#10" class="mim-tip-reference" title="Gwack, Y., Sharma, S., Nardone, J., Tanasa, B., Iuga, A., Srikanth, S., Okamura, H., Bolton, D., Feske, S., Hogan, P. G., Rao, A. <strong>A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT.</strong> Nature 441: 646-650, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16511445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16511445</a>] [<a href="https://doi.org/10.1038/nature04631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16511445">Gwack et al. (2006)</a> concluded that genetic screening in Drosophila can be successfully applied to cross evolutionary boundaries and identify new regulators of a transcription factor that is expressed only in vertebrates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16511445" 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="#22" class="mim-tip-reference" title="Ryoo, S.-R., Jeong, H. K., Radnaabazar, C., Yoo, J.-J., Cho, H.-J., Lee, H.-W., Kim, I.-S., Cheon, Y.-H., Ahn, Y. S., Chung, S.-H., Song, W.-J. <strong>DYRK1A-mediated hyperphosphorylation of tau: a functional link between Down syndrome and Alzheimer disease.</strong> J. Biol. Chem. 282: 34850-34857, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17906291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17906291</a>] [<a href="https://doi.org/10.1074/jbc.M707358200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17906291">Ryoo et al. (2007)</a> showed that mice overexpressing human DYRK1A had elevated levels of threonine-phosphorylated tau (MAPT; <a href="/entry/157140">157140</a>), which is found in insoluble neurofibrillary tangles in Alzheimer disease brains. DYRK1A phosphorylated tau on threonine and serine residues in vitro. Phosphorylation of tau by DYRK1A reduced the ability of tau to promote microtubule assembly. <a href="#22" class="mim-tip-reference" title="Ryoo, S.-R., Jeong, H. K., Radnaabazar, C., Yoo, J.-J., Cho, H.-J., Lee, H.-W., Kim, I.-S., Cheon, Y.-H., Ahn, Y. S., Chung, S.-H., Song, W.-J. <strong>DYRK1A-mediated hyperphosphorylation of tau: a functional link between Down syndrome and Alzheimer disease.</strong> J. Biol. Chem. 282: 34850-34857, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17906291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17906291</a>] [<a href="https://doi.org/10.1074/jbc.M707358200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17906291">Ryoo et al. (2007)</a> concluded that an extra copy of DYRK1A can contribute to early onset of Alzheimer disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17906291" 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 transchromosomic mouse model of Down syndrome, <a href="#4" class="mim-tip-reference" title="Canzonetta, C., Mulligan, C., Deutsch, S., Ruf, S., O'Doherty, A., Lyle, R., Borel, C., Lin-Marq, N., Delom, F., Groet, J., Schnappauf, F., De Vita, S, and 12 others. <strong>DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.</strong> Am. J. Hum. Genet. 83: 388-400, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18771760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18771760</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18771760[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.08.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18771760">Canzonetta et al. (2008)</a> showed that a 30 to 60% reduced expression of NRSF/REST (<a href="/entry/600571">600571</a>), a key regulator of pluripotency and neuronal differentiation, is an alteration that persists in trisomy 21 from undifferentiated embryonic stem cells to adult brain and is reproducible across several Down syndrome models. Using partially trisomic embryonic stem (ES) cells, <a href="#4" class="mim-tip-reference" title="Canzonetta, C., Mulligan, C., Deutsch, S., Ruf, S., O'Doherty, A., Lyle, R., Borel, C., Lin-Marq, N., Delom, F., Groet, J., Schnappauf, F., De Vita, S, and 12 others. <strong>DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.</strong> Am. J. Hum. Genet. 83: 388-400, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18771760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18771760</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18771760[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.08.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18771760">Canzonetta et al. (2008)</a> mapped this effect to a 3-gene segment of human chromosome 21 containing DYRK1A. The authors independently identified the same locus as the most significant expression quantitative trait locus (eQTL) controlling REST expression in the human genome. <a href="#4" class="mim-tip-reference" title="Canzonetta, C., Mulligan, C., Deutsch, S., Ruf, S., O'Doherty, A., Lyle, R., Borel, C., Lin-Marq, N., Delom, F., Groet, J., Schnappauf, F., De Vita, S, and 12 others. <strong>DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.</strong> Am. J. Hum. Genet. 83: 388-400, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18771760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18771760</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18771760[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.08.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18771760">Canzonetta et al. (2008)</a> found that specifically silencing the third copy of DYRK1A rescued Rest levels, and demonstrated altered Rest expression in response to inhibition of DYRK1A expression or kinase activity, and in a transgenic Dyrk1a mouse. The authors observed that undifferentiated trisomy 21 ES cells showed DYRK1A-dose-sensitive reductions in levels of some pluripotency regulators, including Nanog (<a href="/entry/607937">607937</a>) and Sox2 (<a href="/entry/184429">184429</a>), causing premature expression of transcription factors driving early endodermal and mesodermal differentiation, partially overlapping downstream effects of Rest heterozygosity. The ES cells produced embryoid bodies with elevated levels of the primitive endoderm progenitor marker Gata4 (<a href="/entry/600576">600576</a>) and a strongly reduced neuroectodermal progenitor compartment. <a href="#4" class="mim-tip-reference" title="Canzonetta, C., Mulligan, C., Deutsch, S., Ruf, S., O'Doherty, A., Lyle, R., Borel, C., Lin-Marq, N., Delom, F., Groet, J., Schnappauf, F., De Vita, S, and 12 others. <strong>DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.</strong> Am. J. Hum. Genet. 83: 388-400, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18771760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18771760</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18771760[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.08.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18771760">Canzonetta et al. (2008)</a> concluded that DYRK1A-mediated deregulation of REST is a very early pathologic consequence of trisomy 21 with potential to disturb the development of all embryonic lineages, warranting closer research into its contribution to Down syndrome pathology and new rationales for therapeutic approaches. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18771760" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By varying Dyrk1a gene dosage in mice, <a href="#14" class="mim-tip-reference" title="Laguna, A., Aranda, S., Barallobre, M. J., Barhoum, R., Fernandez, E., Fotaki, V., Delabar, J. M., de la Luna, S., de la Villa, P., Arbones, M. L. <strong>The protein kinase DYRK1A regulates caspase-9-mediated apoptosis during retina development.</strong> Dev. Cell 15: 841-853, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19081073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19081073</a>] [<a href="https://doi.org/10.1016/j.devcel.2008.10.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19081073">Laguna et al. (2008)</a> showed that variations in Dyrk1a expression in retina led to a dose-dependent increase in retinal inner cell number and altered retinal activity. Inner retinal cells were generated normally in mice under- or overexpressing Dyrk1a; however, overexpression of Dyrk1a resulted in inhibitory threonine phosphorylation of caspase-9 (CASP9; <a href="/entry/602234">602234</a>), leading to reduced apoptosis and increased cell number. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19081073" 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="Baek, K.-H., Zaslavsky, A., Lynch, R. C., Britt, C., Okada, Y., Siarey, R. J., Lensch, M. W., Park, I.-H., Yoon, S. S., Minami, T., Korenberg, J. R., Folkman, J., Daley, G. Q., Aird, W. C., Galdzicki, Z., Ryeom, S. <strong>Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1.</strong> Nature 459: 1126-1130, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19458618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19458618</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19458618[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/nature08062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19458618">Baek et al. (2009)</a> demonstrated that DSCR1 expression is increased in Down syndrome tissues and in a mouse model of Down syndrome. Furthermore, the modest increase in expression afforded by a single extra transgenic copy of Dscr1 in mice is sufficient to confer significant suppression of tumor growth, and such resistance is a consequence of a deficit in tumor angiogenesis arising from suppression of the calcineurin pathway. <a href="#3" class="mim-tip-reference" title="Baek, K.-H., Zaslavsky, A., Lynch, R. C., Britt, C., Okada, Y., Siarey, R. J., Lensch, M. W., Park, I.-H., Yoon, S. S., Minami, T., Korenberg, J. R., Folkman, J., Daley, G. Q., Aird, W. C., Galdzicki, Z., Ryeom, S. <strong>Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1.</strong> Nature 459: 1126-1130, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19458618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19458618</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19458618[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/nature08062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19458618">Baek et al. (2009)</a> also provided evidence that attenuation of calcineurin activity by DSCR1, together with another chromosome 21 gene Dyrk1a, may be sufficient to markedly diminish angiogenesis. <a href="#3" class="mim-tip-reference" title="Baek, K.-H., Zaslavsky, A., Lynch, R. C., Britt, C., Okada, Y., Siarey, R. J., Lensch, M. W., Park, I.-H., Yoon, S. S., Minami, T., Korenberg, J. R., Folkman, J., Daley, G. Q., Aird, W. C., Galdzicki, Z., Ryeom, S. <strong>Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1.</strong> Nature 459: 1126-1130, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19458618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19458618</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19458618[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/nature08062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19458618">Baek et al. (2009)</a> concluded that their data provided a mechanism for the reduced cancer incidence of Down syndrome and identified the calcineurin signaling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancer arising in all individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19458618" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Scales, T. M. E., Lin, S., Kraus, M., Goold, R. G., Gordon-Weeks, P. R. <strong>Nonprimed and DYRK1A-primed GSK3-beta-phosphorylation sites on MAP1B regulate microtubule dynamics in growing axons.</strong> J. Cell Sci. 122: 2424-2435, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19549690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19549690</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19549690[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/jcs.040162" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19549690">Scales et al. (2009)</a> found that Dyrk1a phosphorylated Map1b (<a href="/entry/157129">157129</a>) at S1392 to prime Map1b for subsequent phosphorylation by Gsk3-beta (GSK3B; <a href="/entry/605004">605004</a>) at S1388 in cultured rat embryonic cortical neurons. Further analysis demonstrated that Dyrk1a-primed and nonprimed Gsk3-beta phosphorylation sites were involved in regulation of microtubule stability in growing cortical neuronal axons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19549690" 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 woman with autosomal dominant intellectual developmental disorder-7 (MRD7; <a href="/entry/614104">614104</a>), microcephaly, and dysmorphic features, <a href="#29" class="mim-tip-reference" title="van Bon, B. W. M., Hoischen, A., Hehir-Kwa, J., de Brouwer, A. P. M., Ruivenkamp, C., Gijsbers, A. C. J., Marcelis, C. L., de Leeuw, N., Veltman, J. A., Brunner, H. G., de Vries, B. B. A. <strong>Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly.</strong> Clin. Genet. 79: 296-299, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21294719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21294719</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2010.01544.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21294719">van Bon et al. (2011)</a> identified a de novo heterozygous 52-kb deletion in the DYRK1A gene (<a href="#0001">600855.0001</a>). This patient was identified among a larger group of 3,009 mentally retarded individuals studied for copy number variations in the DYRK1A gene. The report supported a role for DYRK1A in human brain development and showed that haploinsufficiency of DYRK1A can cause a distinctive clinical syndrome with mental retardation, primary microcephaly, intrauterine growth retardation, facial dysmorphism, impaired motor functioning, and behavioral problems. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21294719" 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="#19" class="mim-tip-reference" title="O'Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., Munson, J., Hiatt, J. B., and 14 others. <strong>Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.</strong> Science 338: 1619-1622, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23160955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23160955</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23160955[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1227764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23160955">O'Roak et al. (2012)</a> identified 3 de novo mutations in DYRK1A, 2 frameshift and 1 splice site mutation (<a href="#0002">600855.0002</a>-<a href="#0004">600855.0004</a>), among 44 candidate gene sequences in 2,446 autism spectrum disorder probands. The 3 patients with DYRK1A mutations had microcephaly relative to individuals screened without DYRK1A mutations (2-sample permutation test, 2-sided p = 0.0005), and the head sizes of these patients was smaller than those of their parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23160955" 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="#18" class="mim-tip-reference" title="Moller, R. S., Kubart, S., Hoeltzenbein, M., Heye, B., Vogel, I., Hansen, C. P., Menzel, C., Ullmann, R., Tommerup, N., Ropers, H.-H., Tumer, Z., Kalscheuer, V. M. <strong>Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly.</strong> Am. J. Hum. Genet. 82: 1165-1170, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18405873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18405873</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18405873[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.03.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18405873">Moller et al. (2008)</a> reported 2 unrelated patients with microcephaly, intrauterine growth retardation, postnatal feeding difficulties, and dysmorphic facial features (see <a href="/entry/614104">614104</a>) who each had a de novo balanced translocation disrupting the DYRK1A gene: t(9;21)(p12;q22) and t(2;21)(q22;q22), respectively. In the second patient, the 2q22 breakpoint was within intron 39 of the LRP1B (<a href="/entry/608766">608766</a>) gene. The first child, 24 months old at the time of the report, had large low-set ears, long philtrum, micrognathia, hypogenesis of the corpus callosum, mild developmental delay, and febrile seizures. The second child, age 10 years, had large ears, flat philtrum, asymmetric head, febrile seizures, severe mental retardation, no speech development, and a small ventricular septal defect. <a href="#18" class="mim-tip-reference" title="Moller, R. S., Kubart, S., Hoeltzenbein, M., Heye, B., Vogel, I., Hansen, C. P., Menzel, C., Ullmann, R., Tommerup, N., Ropers, H.-H., Tumer, Z., Kalscheuer, V. M. <strong>Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly.</strong> Am. J. Hum. Genet. 82: 1165-1170, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18405873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18405873</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18405873[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.03.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18405873">Moller et al. (2008)</a> noted the phenotypic similarities to patients with partial monosomy 21 (<a href="#17" class="mim-tip-reference" title="Matsumoto, N., Ohashi, H., Tsukahara, M., Kim, K. C., Soeda, E., Niikawa, N. <strong>Possible narrowed assignment of the loci of monosomy 21-associated microcephaly and intrauterine growth retardation to a 1.2-Mb segment at 21q22.2. (Letter)</strong> Am. J. Hum. Genet. 60: 997-999, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9106547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9106547</a>]" pmid="9106547">Matsumoto et al., 1997</a>) and suggested that haploinsufficiency of the DYRK1A gene results in microcephaly as well as other neurodevelopmental anomalies. <a href="#29" class="mim-tip-reference" title="van Bon, B. W. M., Hoischen, A., Hehir-Kwa, J., de Brouwer, A. P. M., Ruivenkamp, C., Gijsbers, A. C. J., Marcelis, C. L., de Leeuw, N., Veltman, J. A., Brunner, H. G., de Vries, B. B. A. <strong>Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly.</strong> Clin. Genet. 79: 296-299, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21294719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21294719</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2010.01544.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21294719">Van Bon et al. (2011)</a> noted that their patient clearly resembles the 2 patients reported by <a href="#18" class="mim-tip-reference" title="Moller, R. S., Kubart, S., Hoeltzenbein, M., Heye, B., Vogel, I., Hansen, C. P., Menzel, C., Ullmann, R., Tommerup, N., Ropers, H.-H., Tumer, Z., Kalscheuer, V. M. <strong>Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly.</strong> Am. J. Hum. Genet. 82: 1165-1170, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18405873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18405873</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18405873[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.03.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18405873">Moller et al. (2008)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9106547+18405873+21294719" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Courcet, J.-B., Faivre, L., Malzac, P., Masurel-Paulet, A., Lopez, E., Callier, P., Lambert, L., Lemesle, M., Thevenon, J., Gigot, N., Duplomb, L., Ragon, C., Marle, N., Mosca-Boidron, A.-L., Huet, F., Philippe, C., Moncla, A., Thauvin-Robinet, C. <strong>The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy.</strong> J. Med. Genet. 49: 731-736, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23099646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23099646</a>] [<a href="https://doi.org/10.1136/jmedgenet-2012-101251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23099646">Courcet et al. (2012)</a> reported a 4-year-old child with poor growth, microcephaly (-6 SD), severe mental retardation, seizures, facial dysmorphism, and behavioral abnormalities associated with a de novo heterozygous 69-kb deletion of chromosome 21q22.13 including the 5-prime region of the DYRK1A gene. She had feeding difficulties in infancy, hypotonia, delayed walking, and delayed speech. Facial features included thick lips, bulbous nose, mild hypotelorism, micrognathia, prominent incisors, and large ears with a thick helix. Brain MRI was normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23099646" 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="#8" class="mim-tip-reference" title="Green, R. E., Krause, J., Briggs, A. W., Maricic, T., Stenzel, U., Kircher, M., Patterson, N., Li, H., Zhai, W., Fritz, M. H.-Y., Hansen, N. F., Durand, E. Y., and 44 others. <strong>A draft sequence of the Neandertal genome.</strong> Science 328: 710-722, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20448178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20448178</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20448178[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1188021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20448178">Green et al. (2010)</a> published a draft sequence of the Neandertal genome. Comparisons of the Neandertal genome to the genomes of 5 present-day humans from different parts of the world identified a number of genomic regions that may have been affected by positive selection in ancestral modern humans, including genes involved in metabolism and in cognitive and skeletal development. <a href="#8" class="mim-tip-reference" title="Green, R. E., Krause, J., Briggs, A. W., Maricic, T., Stenzel, U., Kircher, M., Patterson, N., Li, H., Zhai, W., Fritz, M. H.-Y., Hansen, N. F., Durand, E. Y., and 44 others. <strong>A draft sequence of the Neandertal genome.</strong> Science 328: 710-722, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20448178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20448178</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20448178[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1188021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20448178">Green et al. (2010)</a> identified a total of 212 regions containing putative selective sweeps. Mutations in several genes in regions of selective sweeps, including DYRK1A, NRG3 (<a href="/entry/605533">605533</a>), CADPS2 (<a href="/entry/609978">609978</a>), and AUTS2 (<a href="/entry/607270">607270</a>), have been associated with disorders affecting cognitive capacities. <a href="#8" class="mim-tip-reference" title="Green, R. E., Krause, J., Briggs, A. W., Maricic, T., Stenzel, U., Kircher, M., Patterson, N., Li, H., Zhai, W., Fritz, M. H.-Y., Hansen, N. F., Durand, E. Y., and 44 others. <strong>A draft sequence of the Neandertal genome.</strong> Science 328: 710-722, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20448178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20448178</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20448178[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1188021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20448178">Green et al. (2010)</a> hypothesized that multiple genes involved in cognitive development were positively selected during the early history of modern humans. <a href="#8" class="mim-tip-reference" title="Green, R. E., Krause, J., Briggs, A. W., Maricic, T., Stenzel, U., Kircher, M., Patterson, N., Li, H., Zhai, W., Fritz, M. H.-Y., Hansen, N. F., Durand, E. Y., and 44 others. <strong>A draft sequence of the Neandertal genome.</strong> Science 328: 710-722, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20448178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20448178</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20448178[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1188021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20448178">Green et al. (2010)</a> also showed that Neandertals shared more genetic variants with present-day humans in Eurasia than with present-day humans in sub-Saharan Africa, suggesting that gene flow from Neandertals into the ancestors of non-Africans occurred before the divergence of Eurasian groups from each other. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20448178" 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="#11" class="mim-tip-reference" title="Jiang, J., Jing, Y., Cost, G. J., Chiang, J.-C., Kolpa, H. J., Cotton, A. M., Carone, D. M., Carone, B. R., Shivak, D. A., Guschin, D. Y., Pearl, J. R., Rebar, E. J., Byron, M., Gregory, P. D., Brown, C. J., Urnov, F. D., Hall, L. L., Lawrence, J. B. <strong>Translating dosage compensation to trisomy 21.</strong> Nature 500: 296-300, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23863942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23863942</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23863942[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/nature12394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23863942">Jiang et al. (2013)</a> tested the concept that a gene imbalance across an extra chromosome can be de facto corrected by manipulating a single gene, X inactivation-specific transcript (XIST; <a href="/entry/314670">314670</a>). Using genome editing with zinc finger nucleases, <a href="#11" class="mim-tip-reference" title="Jiang, J., Jing, Y., Cost, G. J., Chiang, J.-C., Kolpa, H. J., Cotton, A. M., Carone, D. M., Carone, B. R., Shivak, D. A., Guschin, D. Y., Pearl, J. R., Rebar, E. J., Byron, M., Gregory, P. D., Brown, C. J., Urnov, F. D., Hall, L. L., Lawrence, J. B. <strong>Translating dosage compensation to trisomy 21.</strong> Nature 500: 296-300, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23863942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23863942</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23863942[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/nature12394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23863942">Jiang et al. (2013)</a> inserted a large inducible XIST transgene into the DYRK1A locus on chromosome 21 in Down syndrome pluripotent stem cells. The XIST noncoding RNA coats chromosome 21 and triggers stable heterochromatin modifications, chromosomewide transcriptional silencing, and DNA methylation to form a 'chromosome 21 Barr body.' This provided a model to study human chromosome inactivation and created a system to investigate genomic expression changes and cellular pathologies of trisomy 21, free from genetic and epigenetic noise. Notably, deficits in proliferation and neural rosette formation are rapidly reversed upon silencing 1 chromosome 21. <a href="#11" class="mim-tip-reference" title="Jiang, J., Jing, Y., Cost, G. J., Chiang, J.-C., Kolpa, H. J., Cotton, A. M., Carone, D. M., Carone, B. R., Shivak, D. A., Guschin, D. Y., Pearl, J. R., Rebar, E. J., Byron, M., Gregory, P. D., Brown, C. J., Urnov, F. D., Hall, L. L., Lawrence, J. B. <strong>Translating dosage compensation to trisomy 21.</strong> Nature 500: 296-300, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23863942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23863942</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23863942[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/nature12394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23863942">Jiang et al. (2013)</a> suggested that their successful trisomy silencing in vitro surmounted the major first step towards potential development of chromosome therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23863942" 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>Using Down syndrome as a model for complex trait analysis, <a href="#25" class="mim-tip-reference" title="Smith, D. J., Stevens, M. E., Sudanagunta, S. P., Bronson, R. T., Makhinson, M., Watabe, A. M., O'Dell, T. J., Fung, J., Weier, H.-U. G., Cheng, J.-F., Rubin, E. M. <strong>Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome.</strong> Nature Genet. 16: 28-36, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9140392/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9140392</a>] [<a href="https://doi.org/10.1038/ng0597-28" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9140392">Smith et al. (1997)</a> sought to identify loci from 21q22.2 which, when present in an extra dose, contribute to learning abnormalities. They generated low-copy number transgenic mice, containing 4 different YACs that together cover approximately 2 Mb of contiguous DNA from 21q22.2. They subjected independent mouse lines derived from each of these YAC transgenes to a series of behavioral and learning assays. Two of the 4 YACs caused defects in learning and memory in the transgenic animals, while the other 2 YACs had no effect. The most severe defects were caused by a 570-kb YAC; the interval responsible for these defects was narrowed to a 180-kb critical region as a consequence of YAC fragmentation. This region was found to contain the human homolog of the Drosophila 'minibrain' gene, and strongly implicated it in learning defects associated with Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9140392" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Altafaj, X., Dierssen, M., Baamonde, C., Marti, E., Visa, J., Guimera, J., Oset, M., Gonzalez, J. R., Florez, J., Fillat, C., Estivill, X. <strong>Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome.</strong> Hum. Molec. Genet. 10: 1915-1923, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11555628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11555628</a>] [<a href="https://doi.org/10.1093/hmg/10.18.1915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11555628">Altafaj et al. (2001)</a> generated transgenic mice overexpressing the full-length cDNA of Dyrk1A. Dyrk1A mice exhibited delayed craniocaudal maturation with functional consequences in neuromotor development. Dyrk1A mice also showed altered motor skill acquisition and hyperactivity, which was maintained to adulthood. In the Morris water maze, Dyrk1A mice showed a significant impairment in spatial learning and cognitive flexibility, indicative of hippocampal and prefrontal cortex dysfunction. In the more complex repeated reversal learning paradigm, this defect was specifically related to reference memory, whereas working memory was almost unimpaired. <a href="#1" class="mim-tip-reference" title="Altafaj, X., Dierssen, M., Baamonde, C., Marti, E., Visa, J., Guimera, J., Oset, M., Gonzalez, J. R., Florez, J., Fillat, C., Estivill, X. <strong>Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome.</strong> Hum. Molec. Genet. 10: 1915-1923, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11555628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11555628</a>] [<a href="https://doi.org/10.1093/hmg/10.18.1915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11555628">Altafaj et al. (2001)</a> suggested a causative role of DYRK1A in mental retardation and in motor anomalies of Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11555628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By gene targeting, <a href="#7" class="mim-tip-reference" title="Fotaki, V., Dierssen, M., Alcantara, S., Martinez, S., Marti, E., Casas, C., Visa, J., Soriano, E., Estivill, X., Arbones, M. L. <strong>Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice.</strong> Molec. Cell. Biol. 22: 6636-6647, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12192061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12192061</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12192061[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/10.1128/MCB.22.18.6636-6647.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12192061">Fotaki et al. (2002)</a> created Dyrk1a-null mice. Homozygous null mutants presented a general growth delay and died during midgestation. Heterozygous mice showed decreased neonatal viability and reduced body size from birth to adulthood. General neurobehavioral analysis revealed preweaning developmental delay in heterozygous mice and specific alterations in adults. Brains of heterozygous mice were decreased in size in a region-specific manner, although the cytoarchitecture and neuronal components in most areas were not altered. Cell counts showed increased neuronal densities in some brain regions and a specific decrease in the number of neurons in the superior colliculus, which exhibited a significant size reduction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12192061" 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 an adeno-associated virus construct that included a small hairpin RNA directed against Dyrk1a, <a href="#20" class="mim-tip-reference" title="Ortiz-Abalia, J., Sahun, I., Altafaj, X., Andreu, N., Estivill, X., Dierssen, M., Fallat, C. <strong>Targeting Dyrk1A with AAVshRNA attenuates motor alterations in TgDyrk1A, a mouse model of Down syndrome.</strong> Am. J. Hum. Genet. 83: 479-488, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18940310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18940310</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18940310[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.09.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18940310">Ortiz-Abalia et al. (2008)</a> downregulated expression of Dyrk1a in transgenic mice overexpressing Dyrk1a as a Down syndrome model. The treatment was devoid of toxicity and normalized Dyrk1a protein levels. Importantly, downregulation of Dyrk1a reversed the corticostriatal-dependent phenotype, as shown by attenuation of hyperactive behavior, restoration of motor-coordination defects, and improved sensorimotor gating. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18940310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Lepagnol-Bestel, A.-M., Zvara, A., Maussion, G., Quignon, F., Ngimbous, B., Ramoz, N., Imbeaud, S., Loe-Mie, Y., Benihoud, K., Agier, N., Salin, P. A., Cardona, A., and 11 others. <strong>DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome.</strong> Hum. Molec. Genet. 18: 1405-1414, 2009. Note: Erratum: Hum. Molec. Genet. 31: 2106-2107, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19218269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19218269</a>] [<a href="https://doi.org/10.1093/hmg/ddp047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19218269">Lepagnol-Bestel et al. (2009)</a> used the transgenic 152F7 mouse model of Down syndrome to show that DYRK1A gene dosage imbalance deregulated chromosomal clusters of genes located near REST REST/NRSF (<a href="/entry/600571">600571</a>) binding sites. Dyrk1a bound the SWI/SNF complex, which is known to interact with REST/NRSF. Mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam (<a href="/entry/308840">308840</a>) modified the transcriptional effect of Dyrk1a-dosage imbalance on L1cam. Dyrk1a dosage imbalance perturbed Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. In transgenic embryonic brain subregions, the authors identified a coordinated deregulation of multiple genes that responsible for dendritic growth impairment. Similarly, Dyrk1a overexpression in primary mouse cortical neurons induced severe reduction of the dendritic growth and dendritic complexity. <a href="#16" class="mim-tip-reference" title="Lepagnol-Bestel, A.-M., Zvara, A., Maussion, G., Quignon, F., Ngimbous, B., Ramoz, N., Imbeaud, S., Loe-Mie, Y., Benihoud, K., Agier, N., Salin, P. A., Cardona, A., and 11 others. <strong>DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome.</strong> Hum. Molec. Genet. 18: 1405-1414, 2009. Note: Erratum: Hum. Molec. Genet. 31: 2106-2107, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19218269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19218269</a>] [<a href="https://doi.org/10.1093/hmg/ddp047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19218269">Lepagnol-Bestel et al. (2009)</a> proposed that both the DYRK1A overexpression-related neuronal gene deregulation (via disturbance of REST/NRSF levels) and the REST/NRSF-SWI/SNF chromatin remodeling complex significantly contribute to the neural phenotypic changes that characterize Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19218269" 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 woman with intellectual developmental disorder-7 (MRD7; <a href="/entry/614104">614104</a>), microcephaly, and dysmorphic features, <a href="#29" class="mim-tip-reference" title="van Bon, B. W. M., Hoischen, A., Hehir-Kwa, J., de Brouwer, A. P. M., Ruivenkamp, C., Gijsbers, A. C. J., Marcelis, C. L., de Leeuw, N., Veltman, J. A., Brunner, H. G., de Vries, B. B. A. <strong>Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly.</strong> Clin. Genet. 79: 296-299, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21294719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21294719</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2010.01544.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21294719">van Bon et al. (2011)</a> identified a de novo heterozygous 52-kb deletion (chr21:37,796,500-37,849,000, NCBI36) of the DYRK1A gene, affecting the last 3 exons. as an infant, she had failure to thrive, abnormal movements, hypoactivity, and febrile seizures. Brain MRI at age 25 showed a mildly atrophic brain without structural abnormalities. Dysmorphic features included bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. This patient was identified among a larger group of 3,009 mentally retarded individuals studied for copy number variations in the DYRK1A gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21294719" 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 96-month-old non-Hispanic white male diagnosed with autism and mental retardation (MRD7; <a href="/entry/614104">614104</a>), <a href="#19" class="mim-tip-reference" title="O'Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., Munson, J., Hiatt, J. B., and 14 others. <strong>Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.</strong> Science 338: 1619-1622, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23160955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23160955</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23160955[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1227764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23160955">O'Roak et al. (2012)</a> identified a de novo heterozygous 2-bp deletion in the DYRK1A gene that resulted in a frameshift and premature termination of the protein (Ile48LysfsTer2). The patient's verbal IQ was 63; nonverbal IQ, 55; and low adaptive score, 74. He had polydactyly and had been hypotonic and lethargic as an infant. He was diagnosed with mild mental retardation and found to be excessively clumsy and uncoordinated. His head circumference was 47.6 cm (z score = -3.8). The patient's father and mother were 55 and 39 years of age, respectively, at the time of his conception. His 13-year-old brother was healthy with a normal head circumference. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23160955" 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 13-year-old non-Hispanic white female with autism and severe mental retardation (MRD7; <a href="/entry/614104">614104</a>), <a href="#19" class="mim-tip-reference" title="O'Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., Munson, J., Hiatt, J. B., and 14 others. <strong>Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.</strong> Science 338: 1619-1622, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23160955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23160955</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23160955[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1227764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23160955">O'Roak et al. (2012)</a> identified a heterozygous de novo splice site mutation in the DYRK1A gene, a G-to-A transition at the 1098+1 position (1098G-A+1). The mutation occurs in the serine/threonine kinase domain. The patient's verbal IQ was 26, nonverbal IQ 42, and adaptive score 41. MRI was normal, but EEG results were unclear. The patient's head circumference was 51.5 cm (z score = -1.6). Her father was 37 at the time of conception and had some evidence of broader autism phenotype with elevated rigid and aloof behaviors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23160955" 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 71-month-old non-Hispanic white male diagnosed with autism (MRD7; <a href="/entry/614104">614104</a>), <a href="#19" class="mim-tip-reference" title="O'Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., Munson, J., Hiatt, J. B., and 14 others. <strong>Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.</strong> Science 338: 1619-1622, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23160955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23160955</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23160955[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1227764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23160955">O'Roak et al. (2012)</a> identified a heterozygous de novo 1-bp deletion in the DYRK1A gene that resulted in a frameshift and premature termination of the protein (Ala498ProfsTer94). The patient had a verbal IQ of 91, nonverbal IQ of 66, and adaptive score of 68. He had a history of speech delay and seizures both febrile and nonfebrile, and had ADHD. His head circumference was 48 cm (z score = -2.7). His father was 37 at the time of conception; his mother was 36. Both were healthy with normal head circumferences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23160955" 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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DYRK1A, 2-BP DEL, 290CT
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1064793546 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1064793546;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=rs1064793546" 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=rs1064793546" 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=RCV000032825 OR RCV000483822 OR RCV001509579" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032825, RCV000483822, RCV001509579" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032825...</a>
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<p>In a 14-year-old girl with severe mental retardation (MRD7; <a href="/entry/614104">614104</a>), <a href="#6" class="mim-tip-reference" title="Courcet, J.-B., Faivre, L., Malzac, P., Masurel-Paulet, A., Lopez, E., Callier, P., Lambert, L., Lemesle, M., Thevenon, J., Gigot, N., Duplomb, L., Ragon, C., Marle, N., Mosca-Boidron, A.-L., Huet, F., Philippe, C., Moncla, A., Thauvin-Robinet, C. <strong>The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy.</strong> J. Med. Genet. 49: 731-736, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23099646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23099646</a>] [<a href="https://doi.org/10.1136/jmedgenet-2012-101251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23099646">Courcet et al. (2012)</a> identified a de novo heterozygous 2-bp deletion (290_291delCT) in exon 3 of the DYRK1A gene, resulting in a frameshift and premature termination (Ser97CysfsTer98). The patient had a history of intrauterine growth retardation and feeding difficulties. She developed seizures of multiple types at age 18 months. Other features included microcephaly (-6 SD), severe speech delay, diffuse cortical atrophy on MRI, hand stereotypies, and facial dysmorphism with thick lower lip, mild hypotelorism, and hypoplastic earlobes. This patient was ascertained from a larger cohort of 150 patients with a similar phenotype; she was the only one who had a mutation in the DYRK1A gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23099646" 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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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>REFERENCES</strong>
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<a id="Altafaj2001" class="mim-anchor"></a>
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<strong>Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome.</strong>
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Hum. Molec. Genet. 10: 1915-1923, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11555628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11555628</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11555628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/10.18.1915" target="_blank">Full Text</a>]
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<a id="Arron2006" class="mim-anchor"></a>
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Arron, J. R., Winslow, M. M., Polleri, A., Chang, C.-P., Wu, H., Gao, X., Neilson, J. R., Chen, L., Heit, J. J., Kim, S. K., Yamasaki, N., Miyakawa, T., Francke, U., Graef, I. A., Crabtree, G. R.
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<strong>NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21.</strong>
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Nature 441: 595-600, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16554754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16554754</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16554754" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature04678" target="_blank">Full Text</a>]
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<a id="Baek2009" class="mim-anchor"></a>
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Baek, K.-H., Zaslavsky, A., Lynch, R. C., Britt, C., Okada, Y., Siarey, R. J., Lensch, M. W., Park, I.-H., Yoon, S. S., Minami, T., Korenberg, J. R., Folkman, J., Daley, G. Q., Aird, W. C., Galdzicki, Z., Ryeom, S.
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<strong>Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1.</strong>
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Nature 459: 1126-1130, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19458618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19458618</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19458618[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19458618" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature08062" target="_blank">Full Text</a>]
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<a id="Canzonetta2008" class="mim-anchor"></a>
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Canzonetta, C., Mulligan, C., Deutsch, S., Ruf, S., O'Doherty, A., Lyle, R., Borel, C., Lin-Marq, N., Delom, F., Groet, J., Schnappauf, F., De Vita, S, and 12 others.
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<strong>DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.</strong>
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Am. J. Hum. Genet. 83: 388-400, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18771760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18771760</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18771760[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18771760" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2008.08.012" target="_blank">Full Text</a>]
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<a id="Chen1997" class="mim-anchor"></a>
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Chen, H., Antonarakis, S. E.
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<strong>Localisation of a human homologue of the Drosophila mnb and rat Dyrk genes to chromosome 21q22.2.</strong>
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Hum. Genet. 99: 262-265, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9048932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9048932</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9048932" 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/10.1007/s004390050350" target="_blank">Full Text</a>]
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<a id="Courcet2012" class="mim-anchor"></a>
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Courcet, J.-B., Faivre, L., Malzac, P., Masurel-Paulet, A., Lopez, E., Callier, P., Lambert, L., Lemesle, M., Thevenon, J., Gigot, N., Duplomb, L., Ragon, C., Marle, N., Mosca-Boidron, A.-L., Huet, F., Philippe, C., Moncla, A., Thauvin-Robinet, C.
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<strong>The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy.</strong>
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J. Med. Genet. 49: 731-736, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23099646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23099646</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23099646" 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/10.1136/jmedgenet-2012-101251" target="_blank">Full Text</a>]
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<a id="Fotaki2002" class="mim-anchor"></a>
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<div class="">
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Fotaki, V., Dierssen, M., Alcantara, S., Martinez, S., Marti, E., Casas, C., Visa, J., Soriano, E., Estivill, X., Arbones, M. L.
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<strong>Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice.</strong>
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Molec. Cell. Biol. 22: 6636-6647, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12192061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12192061</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12192061[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12192061" 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/10.1128/MCB.22.18.6636-6647.2002" target="_blank">Full Text</a>]
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Green, R. E., Krause, J., Briggs, A. W., Maricic, T., Stenzel, U., Kircher, M., Patterson, N., Li, H., Zhai, W., Fritz, M. H.-Y., Hansen, N. F., Durand, E. Y., and 44 others.
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[<a href="https://doi.org/10.1126/science.1188021" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1999.5775" target="_blank">Full Text</a>]
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Gwack, Y., Sharma, S., Nardone, J., Tanasa, B., Iuga, A., Srikanth, S., Okamura, H., Bolton, D., Feske, S., Hogan, P. G., Rao, A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16511445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16511445</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16511445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature04631" target="_blank">Full Text</a>]
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<a id="Jiang2013" class="mim-anchor"></a>
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Jiang, J., Jing, Y., Cost, G. J., Chiang, J.-C., Kolpa, H. J., Cotton, A. M., Carone, D. M., Carone, B. R., Shivak, D. A., Guschin, D. Y., Pearl, J. R., Rebar, E. J., Byron, M., Gregory, P. D., Brown, C. J., Urnov, F. D., Hall, L. L., Lawrence, J. B.
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Nature 500: 296-300, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23863942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23863942</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23863942[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23863942" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature12394" target="_blank">Full Text</a>]
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<a id="Kelly2005" class="mim-anchor"></a>
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<div class="">
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Kelly, P. A., Rahmani, Z.
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<strong>DYRK1A enhances the mitogen-activated protein kinase cascade in PC12 cells by forming a complex with Ras, B-Raf, and MEK1.</strong>
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[<a href="https://doi.org/10.1091/mbc.e04-12-1085" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M606147200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.devcel.2008.10.014" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature16475" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2008.03.001" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1227764" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M707358200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1242/jcs.040162" target="_blank">Full Text</a>]
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<a id="28" class="mim-anchor"></a>
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<a id="Tejedor1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tejedor, F., Zhu, X. R., Kaltenbach, E., Ackermann, A., Baumann, A., Canal, I., Heisenberg, M., Fischbach, K. F., Pongs, O.
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<strong>Minibrain: a new protein kinase family involved in postembryonic neurogenesis in Drosophila.</strong>
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Neuron 14: 287-301, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7857639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7857639</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7857639" 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/10.1016/0896-6273(95)90286-4" target="_blank">Full Text</a>]
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<a id="29" class="mim-anchor"></a>
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<a id="van Bon2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van Bon, B. W. M., Hoischen, A., Hehir-Kwa, J., de Brouwer, A. P. M., Ruivenkamp, C., Gijsbers, A. C. J., Marcelis, C. L., de Leeuw, N., Veltman, J. A., Brunner, H. G., de Vries, B. B. A.
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<strong>Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly.</strong>
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Clin. Genet. 79: 296-299, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21294719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21294719</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21294719" 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/10.1111/j.1399-0004.2010.01544.x" target="_blank">Full Text</a>]
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</p>
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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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Bao Lige - updated : 07/21/2020
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 06/06/2017<br>Ada Hamosh - updated : 10/3/2013<br>Cassandra L. Kniffin - updated : 1/30/2013<br>Ada Hamosh - updated : 1/23/2013<br>Cassandra L. Kniffin - updated : 7/20/2011<br>Patricia A. Hartz - updated : 10/13/2010<br>Ada Hamosh - updated : 6/9/2010<br>George E. Tiller - updated : 11/30/2009<br>Ada Hamosh - updated : 7/9/2009<br>Ada Hamosh - updated : 12/1/2008<br>Patricia A. Hartz - updated : 10/31/2008<br>Cassandra L. Kniffin - updated : 5/23/2008<br>Ada Hamosh - updated : 7/24/2006<br>Patricia A. Hartz - updated : 10/30/2002<br>George E. Tiller - updated : 1/30/2002<br>Jennifer P. Macke - updated : 5/1/1998<br>Victor A. McKusick - updated : 5/2/1997<br>Victor A. McKusick - updated : 2/19/1997<br>Victor A. McKusick - updated : 2/4/1997<br>Jennifer P. Macke - updated : 10/16/1996
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 10/10/1995
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</span>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 07/29/2022
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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alopez : 04/01/2022<br>carol : 02/15/2022<br>mgross : 07/21/2020<br>carol : 12/14/2017<br>carol : 12/13/2017<br>alopez : 06/06/2017<br>alopez : 06/11/2015<br>carol : 5/23/2014<br>alopez : 10/3/2013<br>carol : 2/6/2013<br>ckniffin : 1/30/2013<br>alopez : 1/24/2013<br>terry : 1/23/2013<br>carol : 11/28/2011<br>wwang : 7/27/2011<br>ckniffin : 7/20/2011<br>mgross : 10/13/2010<br>terry : 10/13/2010<br>alopez : 6/9/2010<br>alopez : 6/9/2010<br>alopez : 6/9/2010<br>wwang : 1/7/2010<br>terry : 11/30/2009<br>alopez : 7/16/2009<br>terry : 7/9/2009<br>alopez : 12/1/2008<br>wwang : 11/6/2008<br>terry : 10/31/2008<br>carol : 9/24/2008<br>wwang : 6/2/2008<br>ckniffin : 5/23/2008<br>alopez : 7/31/2006<br>alopez : 7/31/2006<br>alopez : 7/31/2006<br>alopez : 7/31/2006<br>terry : 7/24/2006<br>mgross : 10/30/2002<br>mgross : 10/30/2002<br>cwells : 2/5/2002<br>cwells : 1/30/2002<br>carol : 7/16/1999<br>psherman : 2/8/1999<br>carol : 11/23/1998<br>alopez : 5/1/1998<br>terry : 7/8/1997<br>mark : 5/2/1997<br>terry : 4/29/1997<br>mark : 2/19/1997<br>terry : 2/11/1997<br>jenny : 2/4/1997<br>terry : 1/17/1997<br>mark : 1/15/1997<br>carol : 10/16/1996<br>mark : 10/16/1996<br>terry : 11/6/1995<br>mark : 10/10/1995
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</span>
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<span class="mim-font">
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<strong>*</strong> 600855
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<div>
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<h3>
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<span class="mim-font">
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DUAL-SPECIFICITY TYROSINE PHOSPHORYLATION-REGULATED KINASE 1A; DYRK1A
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</h3>
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<div>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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DUAL-SPECIFICITY TYROSINE PHOSPHORYLATION-REGULATED KINASE 1; DYRK1<br />
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DUAL-SPECIFICITY TYROSINE PHOSPHORYLATION-REGULATED KINASE; DYRK<br />
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MNB PROTEIN KINASE, SERINE/THREONINE-SPECIFIC<br />
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MINIBRAIN, DROSOPHILA, HOMOLOG OF; MNB; MNBH
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: DYRK1A</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1179301003;
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<strong>
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<em>
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Cytogenetic location: 21q22.13
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Genomic coordinates <span class="small">(GRCh38)</span> : 21:37,365,573-37,526,358 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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21q22.13
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<span class="mim-font">
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Intellectual developmental disorder, autosomal dominant 7
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<span class="mim-font">
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614104
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<span class="mim-font">
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>The DYRK1A gene encodes a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family and participates in various cellular processes. It is a highly conserved gene located in the so-called Down Syndrome critical region (DSCR), a part of chromosome 21 that is responsible for the majority of phenotypic features in Down syndrome (190685) (summary by van Bon et al., 2011). </p>
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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 class="mim-text-font">
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<p>In the course of cloning transcripts from the region of human chromosome 21 that is homologous to the region of mouse chromosome 16 containing the 'weaver' (wv) locus (see 600877), Patil et al. (1995) identified a gene that encodes a serine/threonine-specific protein kinase. The closest relative of this kinase was found to be the Drosophila 'minibrain' gene (mnb) (Tejedor et al., 1995). </p><p>Shindoh et al. (1996) performed exon trapping to find exons within YAC clones spanning the 2-Mb Down syndrome critical region of human chromosome 21. Of more than 160 exons isolated, they found 6 that had significant identity at the amino acid level to the Drosophila 'minibrain' gene. Using 1 of these exons as a probe, they cloned the full-length human cDNA from a human fetal brain cDNA library. Sequence analysis of this cDNA revealed an open reading frame encoding a polypeptide of 754 amino acids. Shindoh et al. (1996) stated that this gene, termed MNB by them, represents the human homolog of the Drosophila mnb gene and of the rat Dyrk gene. The rat Dyrk gene differs from it by only 4 amino acids. Northern blot analysis of MNB revealed 2 transcripts of 6.0 and 7.5 kb. The 6.0-kb transcript was found to be present in all tissues examined, with highest levels of expression in skeletal muscle, testis, fetal lung, and fetal kidney. The 7.5-kb transcript was found to be expressed at a relatively lower level and was found only in adult heart, placenta, spleen, and testis. Shindoh et al. (1996) concluded that the human MNB protein may play a significant role in a signaling pathway regulating cell proliferation and may be involved in normal brain development and in the pathogenesis of Down syndrome. </p><p>Song et al. (1996) cloned the DYRK gene and its murine counterpart (Dyrk) and compared it to the rat Dyrk gene. The 3 mammalian genes are highly conserved, being more than 99% identical at the protein level over their 763-amino acid open reading frame; in addition, the mammalian genes are 83% identical over 414 amino acids to the smaller 542-amino acid mnb protein of Drosophila. The predicted human and murine proteins both contain a nuclear targeting signal sequence, a protein kinase domain, a putative leucine zipper motif, and a highly conservative 13-consecutive-histidine repeat. Northern blot analysis indicated that both human and murine genes encode approximately 6-kb transcripts. PCR screening of cDNA libraries derived from various human and murine tissues indicated that DYRK and Dyrk are expressed both during development and in the adult. In situ hybridization of Dyrk to mouse embryos (days 13, 15, and 17 postcoitus) indicated a differential spatial and temporal pattern of expression, with the most abundant signal localized in brain matter, spinal cord, and retina. The observed expression pattern was coincident with many of the clinical findings in trisomy 21. </p><p>Song et al. (1997) found that mouse Dyrk is expressed in frontal brain nuclei during mouse embryogenesis and that it interacts with other proteins. The chromosomal locus of DYRK, its homology to the mnb gene, and the in situ hybridization expression patterns of murine Dyrk, combined with the fact that transgenic mice for a YAC to which Dyrk maps are mentally deficient, suggested to Song et al. (1996) that DYRK may be involved in the abnormal neurogenesis found in Down syndrome. They considered DYRK a good candidate to mediate some of the pleiotropic effects of Down syndrome. </p><p>Chen and Antonarakis (1997) used exon trapping to identify human chromosome 21-encoded genes and identified in this way the homolog of the Drosophila mnb gene. By Northern analysis they found high expression levels of a 6.8-kb RNA transcript in adult heart, brain, placenta, and skeletal muscle, and in fetal lung, liver, and kidney. </p><p>Using a combination of cDNA library screening and RACE, Guimera et al. (1999) identified 2 transcription start sites, resulting in MNBHa and MNBHb transcripts. Northern blot analysis of multiple tissues using a probe specific to MNBHa revealed ubiquitous expression, while a probe specific to MNBHb revealed expression only in heart and skeletal muscle. Guimera et al. (1999) also identified at least 4 protein isoforms arising from alternative splicing of the C terminus. All isoforms contain a PEST sequence, which potentially directs rapid degradation of the protein. The most abundant transcript in brain produces the largest isoform (isoform-1), a 763-amino acid protein with a calculated molecular mass of about 85.6 kD. This isoform also contains a histidine repeat and a serine/threonine domain not found in the other isoforms. Guimera et al. (1999) determined that the MNBH variant reported by Shindoh et al. (1996) is 9 amino acids shorter than isoform-1 near the N terminus and results from the use of an alternative splice acceptor site. </p><p>Lee et al. (2016) reported that DYRK1A and DYRK1B (604556) kinases phosphorylate ID2 (600386) on threonine-27 (thr27). Hypoxia downregulates this phosphorylation via inactivation of DYRK1A and DYRK1B. The activity of these kinases is stimulated in normoxia by the oxygen-sensing prolyl hydroxylase PHD1 (EGLN2; 606424). ID2 binds to the VHL (608537) ubiquitin ligase complex, displaces VHL-associated cullin-2 (603135), and impairs HIF2-alpha (603349) ubiquitylation and degradation. Phosphorylation of thr27 of ID2 by DYRK1 blocks ID2-VHL interaction and preserves HIF2-alpha ubiquitylation. In glioblastoma, ID2 positively modulates HIF2-alpha activity. Conversely, elevated expression of DYRK1 phosphorylates thr27 of ID2, leading to HIF2-alpha destabilization, loss of glioma stemness, inhibition of tumor growth, and a more favorable outcome for patients with glioblastoma. </p>
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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>Guimera et al. (1999) determined that the MNBH gene contains 17 alternatively spliced exons and spans 150 kb. The 5-prime untranslated region contains 2 separate promoters. One promoter, utilized by the MNBHa variant, contains a GC-rich element and no canonic TATA or CAAT boxes. The other, utilized by MNBHb, contains a CAAT box and a nonconsensus AT-rich motif. </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>Using fluorescence in situ hybridization and regional mapping data, Song et al. (1996) localized the DYRK gene between markers D21S336 and D21S337 in the 21q22.2 region. With amplification by PCR and hybridization analysis, Chen and Antonarakis (1997) mapped the human MNB gene on YACs located on 21q22.2. </p><p>Song et al. (1997) mapped the murine Dyrk gene to distal mouse chromosome 16, in agreement with the mapping of human DYRK to a syntenic region of chromosome 21. </p>
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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>Gene Function</strong>
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</span>
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</h4>
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<p>Kelly and Rahmani (2005) found that overexpression of human DYRK1A in PC12 rat pheochromocytoma cells potentiated their neuronal differentiation in response to nerve growth factor (see NGFB; 162030). Differentiation required upregulation of the Ras (HRAS; 190020)/MAP kinase (see MAPK1; 176948) signaling pathway, but was independent of DYRK1A kinase activity. DYRK1A prolonged Erk (see MAPK3; 601795) activation by interacting with Ras, Braf (164757), and Mek1 (MAP2K1; 176872) to facilitate formation of a Ras/Braf/Mek1 multiprotein complex. </p><p>Using rat hippocampal and mouse neoblastoma cell lines, Kim et al. (2006) found that Dyrk1a interacted with alpha-synuclein (SNCA; 163890), a component of Lewy bodies, one of the pathologic hallmarks of Parkinson disease (168600), Alzheimer disease (104300), and Lewy-body dementia (127750). Dyrk1a serine phosphorylated alpha-synuclein, and this phosphorylation facilitated its intracytoplasmic aggregation. </p><p>Arron et al. (2006) reported that 2 genes, DSCR1 (RCAN1; 602917) and DYRK1A, that lie within the Down syndrome (190685) critical region of human chromosome 21 act synergistically to prevent nuclear occupancy of NFATc transcription factors (see 600489), which are regulators of vertebrate development. Arron et al. (2006) used mathematical modeling to predict that autoregulation within the pathway accentuates the effects of trisomy of DSCR1 and DYRK1A, leading to failure to activate NFATc target genes under specific conditions. The authors' observations of calcineurin (see 114105)- and Nfatc-deficient mice, Dscr1- and Dyrk1a-overexpressing mice, mouse models of Down syndrome, and human trisomy 21 were consistent with these predictions. Arron et al. (2006) suggested that the 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down syndrome. Arron et al. (2006) concluded that more generally, their observations suggest that the destabilization of regulatory circuits can underlie human disease. </p><p>In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free calcium ion levels, they are dephosphorylated by the calmodulin (114180)-dependent phosphatase calcineurin and translocate to the nucleus. NFAT dephosphorylation by calcineurin is countered by distinct NFAT kinases, among them casein kinase-1 (CK1; 600505), and glycogen synthase kinase-3 (GSK3; see 605004). Gwack et al. (2006) used a genomewide RNA interference screen in Drosophila to identify additional regulators of the signaling pathway leading from calcium ion-calcineurin to NFAT. This screen was successful because the pathways regulating NFAT subcellular localization (calcium ion influx, calcium ion-calmodulin-calcineurin signaling, and NFAT kinases) are conserved across species, even though calcium ion-regulated NFAT proteins are not themselves represented in invertebrates. Using the screen, Gwack et al. (2006) identified DYRKs as novel regulators of NFAT. DYRK1A and DYRK2 (603496) counter calcineurin-mediated dephosphorylation of NFAT1 by directly phosphorylating the conserved serine-proline repeat 3 (SP3) motif of the NFAT regulatory domain, thus priming further phosphorylation of the SP2 and serine-rich region 1 (SRR1) motifs by GSK3 and CK1, respectively. Thus, Gwack et al. (2006) concluded that genetic screening in Drosophila can be successfully applied to cross evolutionary boundaries and identify new regulators of a transcription factor that is expressed only in vertebrates. </p><p>Ryoo et al. (2007) showed that mice overexpressing human DYRK1A had elevated levels of threonine-phosphorylated tau (MAPT; 157140), which is found in insoluble neurofibrillary tangles in Alzheimer disease brains. DYRK1A phosphorylated tau on threonine and serine residues in vitro. Phosphorylation of tau by DYRK1A reduced the ability of tau to promote microtubule assembly. Ryoo et al. (2007) concluded that an extra copy of DYRK1A can contribute to early onset of Alzheimer disease. </p><p>Using a transchromosomic mouse model of Down syndrome, Canzonetta et al. (2008) showed that a 30 to 60% reduced expression of NRSF/REST (600571), a key regulator of pluripotency and neuronal differentiation, is an alteration that persists in trisomy 21 from undifferentiated embryonic stem cells to adult brain and is reproducible across several Down syndrome models. Using partially trisomic embryonic stem (ES) cells, Canzonetta et al. (2008) mapped this effect to a 3-gene segment of human chromosome 21 containing DYRK1A. The authors independently identified the same locus as the most significant expression quantitative trait locus (eQTL) controlling REST expression in the human genome. Canzonetta et al. (2008) found that specifically silencing the third copy of DYRK1A rescued Rest levels, and demonstrated altered Rest expression in response to inhibition of DYRK1A expression or kinase activity, and in a transgenic Dyrk1a mouse. The authors observed that undifferentiated trisomy 21 ES cells showed DYRK1A-dose-sensitive reductions in levels of some pluripotency regulators, including Nanog (607937) and Sox2 (184429), causing premature expression of transcription factors driving early endodermal and mesodermal differentiation, partially overlapping downstream effects of Rest heterozygosity. The ES cells produced embryoid bodies with elevated levels of the primitive endoderm progenitor marker Gata4 (600576) and a strongly reduced neuroectodermal progenitor compartment. Canzonetta et al. (2008) concluded that DYRK1A-mediated deregulation of REST is a very early pathologic consequence of trisomy 21 with potential to disturb the development of all embryonic lineages, warranting closer research into its contribution to Down syndrome pathology and new rationales for therapeutic approaches. </p><p>By varying Dyrk1a gene dosage in mice, Laguna et al. (2008) showed that variations in Dyrk1a expression in retina led to a dose-dependent increase in retinal inner cell number and altered retinal activity. Inner retinal cells were generated normally in mice under- or overexpressing Dyrk1a; however, overexpression of Dyrk1a resulted in inhibitory threonine phosphorylation of caspase-9 (CASP9; 602234), leading to reduced apoptosis and increased cell number. </p><p>Baek et al. (2009) demonstrated that DSCR1 expression is increased in Down syndrome tissues and in a mouse model of Down syndrome. Furthermore, the modest increase in expression afforded by a single extra transgenic copy of Dscr1 in mice is sufficient to confer significant suppression of tumor growth, and such resistance is a consequence of a deficit in tumor angiogenesis arising from suppression of the calcineurin pathway. Baek et al. (2009) also provided evidence that attenuation of calcineurin activity by DSCR1, together with another chromosome 21 gene Dyrk1a, may be sufficient to markedly diminish angiogenesis. Baek et al. (2009) concluded that their data provided a mechanism for the reduced cancer incidence of Down syndrome and identified the calcineurin signaling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancer arising in all individuals. </p><p>Scales et al. (2009) found that Dyrk1a phosphorylated Map1b (157129) at S1392 to prime Map1b for subsequent phosphorylation by Gsk3-beta (GSK3B; 605004) at S1388 in cultured rat embryonic cortical neurons. Further analysis demonstrated that Dyrk1a-primed and nonprimed Gsk3-beta phosphorylation sites were involved in regulation of microtubule stability in growing cortical neuronal axons. </p>
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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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</h4>
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<span class="mim-text-font">
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<p>In a woman with autosomal dominant intellectual developmental disorder-7 (MRD7; 614104), microcephaly, and dysmorphic features, van Bon et al. (2011) identified a de novo heterozygous 52-kb deletion in the DYRK1A gene (600855.0001). This patient was identified among a larger group of 3,009 mentally retarded individuals studied for copy number variations in the DYRK1A gene. The report supported a role for DYRK1A in human brain development and showed that haploinsufficiency of DYRK1A can cause a distinctive clinical syndrome with mental retardation, primary microcephaly, intrauterine growth retardation, facial dysmorphism, impaired motor functioning, and behavioral problems. </p><p>O'Roak et al. (2012) identified 3 de novo mutations in DYRK1A, 2 frameshift and 1 splice site mutation (600855.0002-600855.0004), among 44 candidate gene sequences in 2,446 autism spectrum disorder probands. The 3 patients with DYRK1A mutations had microcephaly relative to individuals screened without DYRK1A mutations (2-sample permutation test, 2-sided p = 0.0005), and the head sizes of these patients was smaller than those of their parents. </p>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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</h4>
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<span class="mim-text-font">
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<p>Moller et al. (2008) reported 2 unrelated patients with microcephaly, intrauterine growth retardation, postnatal feeding difficulties, and dysmorphic facial features (see 614104) who each had a de novo balanced translocation disrupting the DYRK1A gene: t(9;21)(p12;q22) and t(2;21)(q22;q22), respectively. In the second patient, the 2q22 breakpoint was within intron 39 of the LRP1B (608766) gene. The first child, 24 months old at the time of the report, had large low-set ears, long philtrum, micrognathia, hypogenesis of the corpus callosum, mild developmental delay, and febrile seizures. The second child, age 10 years, had large ears, flat philtrum, asymmetric head, febrile seizures, severe mental retardation, no speech development, and a small ventricular septal defect. Moller et al. (2008) noted the phenotypic similarities to patients with partial monosomy 21 (Matsumoto et al., 1997) and suggested that haploinsufficiency of the DYRK1A gene results in microcephaly as well as other neurodevelopmental anomalies. Van Bon et al. (2011) noted that their patient clearly resembles the 2 patients reported by Moller et al. (2008). </p><p>Courcet et al. (2012) reported a 4-year-old child with poor growth, microcephaly (-6 SD), severe mental retardation, seizures, facial dysmorphism, and behavioral abnormalities associated with a de novo heterozygous 69-kb deletion of chromosome 21q22.13 including the 5-prime region of the DYRK1A gene. She had feeding difficulties in infancy, hypotonia, delayed walking, and delayed speech. Facial features included thick lips, bulbous nose, mild hypotelorism, micrognathia, prominent incisors, and large ears with a thick helix. Brain MRI was normal. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Evolution</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>Green et al. (2010) published a draft sequence of the Neandertal genome. Comparisons of the Neandertal genome to the genomes of 5 present-day humans from different parts of the world identified a number of genomic regions that may have been affected by positive selection in ancestral modern humans, including genes involved in metabolism and in cognitive and skeletal development. Green et al. (2010) identified a total of 212 regions containing putative selective sweeps. Mutations in several genes in regions of selective sweeps, including DYRK1A, NRG3 (605533), CADPS2 (609978), and AUTS2 (607270), have been associated with disorders affecting cognitive capacities. Green et al. (2010) hypothesized that multiple genes involved in cognitive development were positively selected during the early history of modern humans. Green et al. (2010) also showed that Neandertals shared more genetic variants with present-day humans in Eurasia than with present-day humans in sub-Saharan Africa, suggesting that gene flow from Neandertals into the ancestors of non-Africans occurred before the divergence of Eurasian groups from each other. </p>
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<h4>
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<span class="mim-font">
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<strong>Other Features</strong>
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</h4>
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<span class="mim-text-font">
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<p>Jiang et al. (2013) tested the concept that a gene imbalance across an extra chromosome can be de facto corrected by manipulating a single gene, X inactivation-specific transcript (XIST; 314670). Using genome editing with zinc finger nucleases, Jiang et al. (2013) inserted a large inducible XIST transgene into the DYRK1A locus on chromosome 21 in Down syndrome pluripotent stem cells. The XIST noncoding RNA coats chromosome 21 and triggers stable heterochromatin modifications, chromosomewide transcriptional silencing, and DNA methylation to form a 'chromosome 21 Barr body.' This provided a model to study human chromosome inactivation and created a system to investigate genomic expression changes and cellular pathologies of trisomy 21, free from genetic and epigenetic noise. Notably, deficits in proliferation and neural rosette formation are rapidly reversed upon silencing 1 chromosome 21. Jiang et al. (2013) suggested that their successful trisomy silencing in vitro surmounted the major first step towards potential development of chromosome therapy. </p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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<span class="mim-text-font">
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<p>Using Down syndrome as a model for complex trait analysis, Smith et al. (1997) sought to identify loci from 21q22.2 which, when present in an extra dose, contribute to learning abnormalities. They generated low-copy number transgenic mice, containing 4 different YACs that together cover approximately 2 Mb of contiguous DNA from 21q22.2. They subjected independent mouse lines derived from each of these YAC transgenes to a series of behavioral and learning assays. Two of the 4 YACs caused defects in learning and memory in the transgenic animals, while the other 2 YACs had no effect. The most severe defects were caused by a 570-kb YAC; the interval responsible for these defects was narrowed to a 180-kb critical region as a consequence of YAC fragmentation. This region was found to contain the human homolog of the Drosophila 'minibrain' gene, and strongly implicated it in learning defects associated with Down syndrome. </p><p>Altafaj et al. (2001) generated transgenic mice overexpressing the full-length cDNA of Dyrk1A. Dyrk1A mice exhibited delayed craniocaudal maturation with functional consequences in neuromotor development. Dyrk1A mice also showed altered motor skill acquisition and hyperactivity, which was maintained to adulthood. In the Morris water maze, Dyrk1A mice showed a significant impairment in spatial learning and cognitive flexibility, indicative of hippocampal and prefrontal cortex dysfunction. In the more complex repeated reversal learning paradigm, this defect was specifically related to reference memory, whereas working memory was almost unimpaired. Altafaj et al. (2001) suggested a causative role of DYRK1A in mental retardation and in motor anomalies of Down syndrome. </p><p>By gene targeting, Fotaki et al. (2002) created Dyrk1a-null mice. Homozygous null mutants presented a general growth delay and died during midgestation. Heterozygous mice showed decreased neonatal viability and reduced body size from birth to adulthood. General neurobehavioral analysis revealed preweaning developmental delay in heterozygous mice and specific alterations in adults. Brains of heterozygous mice were decreased in size in a region-specific manner, although the cytoarchitecture and neuronal components in most areas were not altered. Cell counts showed increased neuronal densities in some brain regions and a specific decrease in the number of neurons in the superior colliculus, which exhibited a significant size reduction. </p><p>Using an adeno-associated virus construct that included a small hairpin RNA directed against Dyrk1a, Ortiz-Abalia et al. (2008) downregulated expression of Dyrk1a in transgenic mice overexpressing Dyrk1a as a Down syndrome model. The treatment was devoid of toxicity and normalized Dyrk1a protein levels. Importantly, downregulation of Dyrk1a reversed the corticostriatal-dependent phenotype, as shown by attenuation of hyperactive behavior, restoration of motor-coordination defects, and improved sensorimotor gating. </p><p>Lepagnol-Bestel et al. (2009) used the transgenic 152F7 mouse model of Down syndrome to show that DYRK1A gene dosage imbalance deregulated chromosomal clusters of genes located near REST REST/NRSF (600571) binding sites. Dyrk1a bound the SWI/SNF complex, which is known to interact with REST/NRSF. Mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam (308840) modified the transcriptional effect of Dyrk1a-dosage imbalance on L1cam. Dyrk1a dosage imbalance perturbed Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. In transgenic embryonic brain subregions, the authors identified a coordinated deregulation of multiple genes that responsible for dendritic growth impairment. Similarly, Dyrk1a overexpression in primary mouse cortical neurons induced severe reduction of the dendritic growth and dendritic complexity. Lepagnol-Bestel et al. (2009) proposed that both the DYRK1A overexpression-related neuronal gene deregulation (via disturbance of REST/NRSF levels) and the REST/NRSF-SWI/SNF chromatin remodeling complex significantly contribute to the neural phenotypic changes that characterize Down syndrome. </p>
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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>5 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 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 7</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DYRK1A, 52-KB DEL
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<br />
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ClinVar: RCV000023041
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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 woman with intellectual developmental disorder-7 (MRD7; 614104), microcephaly, and dysmorphic features, van Bon et al. (2011) identified a de novo heterozygous 52-kb deletion (chr21:37,796,500-37,849,000, NCBI36) of the DYRK1A gene, affecting the last 3 exons. as an infant, she had failure to thrive, abnormal movements, hypoactivity, and febrile seizures. Brain MRI at age 25 showed a mildly atrophic brain without structural abnormalities. Dysmorphic features included bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. This patient was identified among a larger group of 3,009 mentally retarded individuals studied for copy number variations in the DYRK1A gene. </p>
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</span>
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<div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 7</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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DYRK1A, 2-BP DEL, AT
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<br />
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SNP: rs587776929,
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ClinVar: RCV000032822
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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 96-month-old non-Hispanic white male diagnosed with autism and mental retardation (MRD7; 614104), O'Roak et al. (2012) identified a de novo heterozygous 2-bp deletion in the DYRK1A gene that resulted in a frameshift and premature termination of the protein (Ile48LysfsTer2). The patient's verbal IQ was 63; nonverbal IQ, 55; and low adaptive score, 74. He had polydactyly and had been hypotonic and lethargic as an infant. He was diagnosed with mild mental retardation and found to be excessively clumsy and uncoordinated. His head circumference was 47.6 cm (z score = -3.8). The patient's father and mother were 55 and 39 years of age, respectively, at the time of his conception. His 13-year-old brother was healthy with a normal head circumference. </p>
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</span>
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</div>
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<div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 7</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DYRK1A, 1098, G-A, +1
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<br />
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SNP: rs587776930,
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ClinVar: RCV000032823
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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 13-year-old non-Hispanic white female with autism and severe mental retardation (MRD7; 614104), O'Roak et al. (2012) identified a heterozygous de novo splice site mutation in the DYRK1A gene, a G-to-A transition at the 1098+1 position (1098G-A+1). The mutation occurs in the serine/threonine kinase domain. The patient's verbal IQ was 26, nonverbal IQ 42, and adaptive score 41. MRI was normal, but EEG results were unclear. The patient's head circumference was 51.5 cm (z score = -1.6). Her father was 37 at the time of conception and had some evidence of broader autism phenotype with elevated rigid and aloof behaviors. </p>
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</span>
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</div>
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<div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 7</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DYRK1A, 1-BP DEL, C
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<br />
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SNP: rs1057519628,
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ClinVar: RCV000417095
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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 71-month-old non-Hispanic white male diagnosed with autism (MRD7; 614104), O'Roak et al. (2012) identified a heterozygous de novo 1-bp deletion in the DYRK1A gene that resulted in a frameshift and premature termination of the protein (Ala498ProfsTer94). The patient had a verbal IQ of 91, nonverbal IQ of 66, and adaptive score of 68. He had a history of speech delay and seizures both febrile and nonfebrile, and had ADHD. His head circumference was 48 cm (z score = -2.7). His father was 37 at the time of conception; his mother was 36. Both were healthy with normal head circumferences. </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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<h4>
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<span class="mim-font">
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<strong>.0005 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 7</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DYRK1A, 2-BP DEL, 290CT
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<br />
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SNP: rs1064793546,
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ClinVar: RCV000032825, RCV000483822, RCV001509579
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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 14-year-old girl with severe mental retardation (MRD7; 614104), Courcet et al. (2012) identified a de novo heterozygous 2-bp deletion (290_291delCT) in exon 3 of the DYRK1A gene, resulting in a frameshift and premature termination (Ser97CysfsTer98). The patient had a history of intrauterine growth retardation and feeding difficulties. She developed seizures of multiple types at age 18 months. Other features included microcephaly (-6 SD), severe speech delay, diffuse cortical atrophy on MRI, hand stereotypies, and facial dysmorphism with thick lower lip, mild hypotelorism, and hypoplastic earlobes. This patient was ascertained from a larger cohort of 150 patients with a similar phenotype; she was the only one who had a mutation in the DYRK1A gene. </p>
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</span>
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<div>
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<h4>
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van Bon, B. W. M., Hoischen, A., Hehir-Kwa, J., de Brouwer, A. P. M., Ruivenkamp, C., Gijsbers, A. C. J., Marcelis, C. L., de Leeuw, N., Veltman, J. A., Brunner, H. G., de Vries, B. B. A.
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<strong>Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly.</strong>
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Clin. Genet. 79: 296-299, 2011.
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[PubMed: 21294719]
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[Full Text: https://doi.org/10.1111/j.1399-0004.2010.01544.x]
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Bao Lige - updated : 07/21/2020<br>Ada Hamosh - updated : 06/06/2017<br>Ada Hamosh - updated : 10/3/2013<br>Cassandra L. Kniffin - updated : 1/30/2013<br>Ada Hamosh - updated : 1/23/2013<br>Cassandra L. Kniffin - updated : 7/20/2011<br>Patricia A. Hartz - updated : 10/13/2010<br>Ada Hamosh - updated : 6/9/2010<br>George E. Tiller - updated : 11/30/2009<br>Ada Hamosh - updated : 7/9/2009<br>Ada Hamosh - updated : 12/1/2008<br>Patricia A. Hartz - updated : 10/31/2008<br>Cassandra L. Kniffin - updated : 5/23/2008<br>Ada Hamosh - updated : 7/24/2006<br>Patricia A. Hartz - updated : 10/30/2002<br>George E. Tiller - updated : 1/30/2002<br>Jennifer P. Macke - updated : 5/1/1998<br>Victor A. McKusick - updated : 5/2/1997<br>Victor A. McKusick - updated : 2/19/1997<br>Victor A. McKusick - updated : 2/4/1997<br>Jennifer P. Macke - updated : 10/16/1996
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Victor A. McKusick : 10/10/1995
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