2926 lines
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Entry
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- *604142 - TYRO PROTEIN TYROSINE KINASE-BINDING PROTEIN; TYROBP
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- OMIM
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<p>
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<span class="h4">*604142</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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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="#cloning">Cloning and Expression</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/604142">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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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="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 id="mimExternalLinksFold" class="collapse in">
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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=ENSG00000011600;t=ENST00000262629" 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=7305" 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=604142" 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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<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=ENSG00000011600;t=ENST00000262629" 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_001173514,NM_001173515,NM_003332,NM_198125,NR_033390" 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_003332" 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=604142" 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=04996&isoform_id=04996_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/TYROBP" 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/2905994,2905996,4507755,5706450,7531221,15029901,28192415,32880045,38158005,47496631,49457400,158261793,291045272,291045274" 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/O43914" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=7305" 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=ENSG00000011600;t=ENST00000262629" 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=TYROBP" 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=TYROBP" 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+7305" 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/TYROBP" 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:7305" 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/7305" 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=chr19&hgg_gene=ENST00000262629.9&hgg_start=35904403&hgg_end=35908295&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 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:12449" 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://medlineplus.gov/genetics/gene/tyrobp" 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=604142[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 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=604142[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000011600" 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.gwascentral.org/search?q=TYROBP" 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=TYROBP" 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=TYROBP&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/PA37100" 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:12449" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1277211" 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/TYROBP#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:1277211" 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/7305/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=7305" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-061130-2" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7305" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=TYROBP&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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604142
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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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TYRO PROTEIN TYROSINE KINASE-BINDING PROTEIN; TYROBP
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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DNAX-ACTIVATION PROTEIN 12; DAP12
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TYROBP" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TYROBP</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/19/607?start=-3&limit=10&highlight=607">19q13.12</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:35904403-35908295&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'})">19:35,904,403-35,908,295</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
|
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<a href="/geneMap/19/607?start=-3&limit=10&highlight=607">
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19q13.12
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/221770"> 221770 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/604142" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/604142" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
|
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<a id="cloning" class="mim-anchor"></a>
|
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>Natural killer (NK) cells express cell surface receptors that recognize major histocompatibility complex class I peptides (e.g., <a href="/entry/142800">142800</a>) and inhibit NK cell-mediated cytotoxicity. NK cell receptors belong to 2 distinct groups: the immunoglobulin superfamily for the killer cell inhibitory receptors (KIRs; e.g., <a href="/entry/602992">602992</a>), and the C-type lectin superfamily for the NKG2 receptors (e.g., <a href="/entry/161555">161555</a>). These inhibitory receptors possess 'immunoreceptor tyrosine-based inhibitory motifs' (ITIMs) in their cytoplasmic domains that recruit SH2 domain-containing protein-tyrosine phosphatases, resulting in inactivation of NK cells. Certain isoforms of NK cell receptors lack ITIM sequences, and these non-inhibitory receptors activate, rather than inhibit, NK cells. Cell surface immunoglobulin receptors, T-cell antigen receptors (e.g., <a href="/entry/186880">186880</a>), and certain Fc receptors noncovalently associate with small transmembrane proteins, such as CD3-delta (CD3D; <a href="/entry/186790">186790</a>), -gamma (CD3G; <a href="/entry/186740">186740</a>), -epsilon (CD3E; <a href="/entry/186830">186830</a>), -zeta (CD3Z; <a href="/entry/186780">186780</a>), CD79-alpha (<a href="/entry/112205">112205</a>), -beta (<a href="/entry/147245">147245</a>), and FCER1G (<a href="/entry/147139">147139</a>), that contain an 'immunoreceptor tyrosine-based activation motif' (ITAM) sequence and are required for signal transduction by these receptor complexes. <a href="#5" class="mim-tip-reference" title="Lanier, L. L., Corliss, B. C., Wu, J., Leong, C., Phillips, J. H. <strong>Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells.</strong> Nature 391: 703-707, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9490415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9490415</a>] [<a href="https://doi.org/10.1038/35642" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9490415">Lanier et al. (1998)</a> hypothesized that non-inhibitory NK cell receptors might require an associated protein with similar properties to mediate positive signal transduction. By searching an EST database with the protein sequences of CD3D, CD3G, CD3E, CD3Z, and FCER1G, they isolated a human CD1+ dendritic cell EST encoding an ITAM-containing protein, which they named DAP12. The predicted 113-amino acid DAP12 protein is composed of a signal peptide, a 14-amino acid extracellular domain, a transmembrane segment, and a 48-amino acid cytoplasmic domain. Although DAP12 shares less than 25% similarity with the human CD3D, CD3G, CD3E, CD3Z, and FCER1G proteins, its cytoplasmic domain contains a sequence that precisely corresponds to the prototype ITAM consensus. Potential sites for phosphorylation are also present in the DAP12 cytoplasmic region. The transmembrane domain of DAP12 contains the charged amino acid aspartic acid, which is conserved in the transmembrane domain of the CD3 subunits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9490415" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Tomasello, E., Olcese, L., Vely, F., Geourgeon, C., Blery, M., Moqrich, A., Gautheret, D., Djabali, M., Mattei, M.-G., Vivier, E. <strong>Gene structure, expression pattern, and biological activity of mouse killer cell activating receptor-associated protein (KARAP)/DAP-12.</strong> J. Biol. Chem. 273: 34115-34119, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9852069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9852069</a>] [<a href="https://doi.org/10.1074/jbc.273.51.34115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9852069">Tomasello et al. (1998)</a> cloned the full-length coding sequence of mouse Tyrobp, which they called Karap for 'killer cell-activating receptor-associated protein.' The deduced human and mouse TYROBP proteins are 73% identical and are more similar to CD3Z and FCER1G than to other known ITAM-bearing molecules. RT-PCR analysis of a variety of hematopoietic and nonhematopoietic mouse cell lines revealed almost ubiquitous expression of Tyrobp. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9852069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Lanier, L. L., Corliss, B. C., Wu, J., Leong, C., Phillips, J. H. <strong>Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells.</strong> Nature 391: 703-707, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9490415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9490415</a>] [<a href="https://doi.org/10.1038/35642" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9490415">Lanier et al. (1998)</a> demonstrated that the DAP12 protein is expressed on the cell surface as a disulfide-bonded homodimer. DAP12 noncovalently associated with KIR2DS2, a KIR family member that lacks an ITIM. Crosslinking of KIR2DS2/DAP12 complexes, but not of KIR2DS2 alone, resulted in cellular activation, as indicated by tyrosine phosphorylation of cellular proteins and upregulation of early-activation antigens. In addition, crosslinking of KIR2DS2/DAP12 complexes induced tyrosine phosphorylation of DAP12 and resulted in the association of phosphorylated DAP12 with the protein-tyrosine kinase SYK (<a href="/entry/600085">600085</a>). Peptides corresponding to the cytoplasmic domain of DAP12 formed complexes with the protein-tyrosine kinases SYK and ZAP70 (<a href="/entry/176947">176947</a>) only if the tyrosine residues in the ITAM of DAP12 were phosphorylated. Northern blot analysis detected an abundant 0.7-kb DAP12 transcript in human peripheral blood leukocytes and spleen but not in thymus or the other tissues examined. The authors found DAP12 expression in human NK cell lines but not in a T leukemia cell line or a B lymphoblastoid cell line. <a href="#5" class="mim-tip-reference" title="Lanier, L. L., Corliss, B. C., Wu, J., Leong, C., Phillips, J. H. <strong>Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells.</strong> Nature 391: 703-707, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9490415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9490415</a>] [<a href="https://doi.org/10.1038/35642" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9490415">Lanier et al. (1998)</a> suggested that DAP12 associates with the non-inhibitory isoforms of the KIR molecules in NK cells and permits cellular activation through these receptors, in a way similar to the function of the CD3 subunits in the T-cell receptor complex and the CD79 subunits in the B-cell receptor complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9490415" 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>DAP12 associates with the cell surface receptor TREM2 (<a href="/entry/605086">605086</a>), and the DAP12-TREM2 complex is involved in dendritic cell maturation. <a href="#7" class="mim-tip-reference" title="Paloneva, J., Mandelin, J., Kiialainen, A., Bohling, T., Prudlo, J., Hakola, P., Haltia, M., Konttinen, Y. T., Peltonen, L. <strong>DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features.</strong> J. Exp. Med. 198: 669-675, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12925681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12925681</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12925681[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/10.1084/jem.20030027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12925681">Paloneva et al. (2003)</a> analyzed differentiation of peripheral blood mononuclear cells from DAP12- and TREM2-deficient Finnish or German polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; <a href="/entry/221770">221770</a>) patients into osteoclasts. They found that homozygous loss-of-function mutations in DAP12 or TREM2 resulted in inefficient, aberrant, and delayed differentiation into osteoclasts and significantly diminished bone resorption capability in vitro. RT-PCR analysis detected no differences between patient and control cells in the expression of several genes, but expression of DAP12 and TREM2 increased in control cells during osteoclastic differentiation. <a href="#7" class="mim-tip-reference" title="Paloneva, J., Mandelin, J., Kiialainen, A., Bohling, T., Prudlo, J., Hakola, P., Haltia, M., Konttinen, Y. T., Peltonen, L. <strong>DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features.</strong> J. Exp. Med. 198: 669-675, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12925681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12925681</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12925681[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/10.1084/jem.20030027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12925681">Paloneva et al. (2003)</a> concluded that the DAP12-TREM2 signaling complex is important in the differentiation and function of osteoclasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12925681" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Lanier, L. L., Corliss, B. C., Wu, J., Leong, C., Phillips, J. H. <strong>Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells.</strong> Nature 391: 703-707, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9490415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9490415</a>] [<a href="https://doi.org/10.1038/35642" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9490415">Lanier et al. (1998)</a> stated that the human TYROBP genomic sequence is contained within a cosmid (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AD000833" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AD000833</a>) that maps to 19q13.1. By FISH, <a href="#8" class="mim-tip-reference" title="Tomasello, E., Olcese, L., Vely, F., Geourgeon, C., Blery, M., Moqrich, A., Gautheret, D., Djabali, M., Mattei, M.-G., Vivier, E. <strong>Gene structure, expression pattern, and biological activity of mouse killer cell activating receptor-associated protein (KARAP)/DAP-12.</strong> J. Biol. Chem. 273: 34115-34119, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9852069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9852069</a>] [<a href="https://doi.org/10.1074/jbc.273.51.34115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9852069">Tomasello et al. (1998)</a> mapped the mouse Tyrobp gene to 7B. They noted that human 19q13 shows homology of synteny with mouse chromosome 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9490415+9852069" 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>Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL1; <a href="/entry/221770">221770</a>), also known as Nasu-Hakola disease, is a recessively inherited disorder characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. Identification of a shared 153-kb ancestor haplotype in all Finnish disease alleles on 19q13.1 was the first step in characterizing the molecular defect. The TYROBP gene was one of those located in the critical DNA region for PLOSL. <a href="#6" class="mim-tip-reference" title="Paloneva, J., Kestila, M., Wu, J., Salminen, A., Bohling, T., Ruotsalainen, V., Hakola, P., Bakker, A. B. H., Phillips, J. H., Pekkarinen, P., Lanier, L. L., Timonen, T., Peltonen, L. <strong>Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts.</strong> Nature Genet. 25: 357-361, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10888890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10888890</a>] [<a href="https://doi.org/10.1038/77153" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10888890">Paloneva et al. (2000)</a> failed to obtain products by PCR amplification of the coding region of TYROBP in the genomic DNA of Finnish PLOSL patients with primers flanking exons 1-4, whereas exon 5 was amplified normally. This indicated that the patients carried a homozygous deletion encompassing exons 1-4 of TYROBP (<a href="#0001">604142.0001</a>). They located the 5-prime deletion breakpoint 2,900 bp upstream of the initiation methionine, and the 3-prime breakpoint in the last intron of TYROBP, 1,300 bp upstream of the termination codon. Sequence analysis of the 342-bp coding region of TYROBP from the genomic DNA of a Japanese PLOSL patient demonstrated homozygosity for a 1-bp deletion in exon 3 (<a href="#0002">604142.0002</a>). This mutation created a frameshift in the open reading frame, predicting premature termination of the polypeptide chain after 52 amino acids. The mutation also changed the aspartic acid residue in the transmembrane domain that is essential in mediating the interaction between the TYROBP homodimer and the associated ligand-binding receptors on the surface of natural killer (NK) cells. On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class III molecules. No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP. In 1 Norwegian and 1 Swedish patient with the typical clinical features of PLOSL, linkage to 19q13.1 was excluded, and no sign of mutation of TYROBP was found in them or their families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10888890" 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 5 of 6 Japanese patients with PLOSL, <a href="#4" class="mim-tip-reference" title="Kondo, T., Takahashi, K., Kohara, N., Takahashi, Y., Hayashi, S., Takahashi, H., Matsuo, H., Yamazaki, M., Inoue, K., Miyamoto, K., Yamamura, T. <strong>Heterogeneity of presenile dementia with bone cysts (Nasu-Hakola disease): three genetic forms.</strong> Neurology 59: 1105-1107, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12370476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12370476</a>] [<a href="https://doi.org/10.1212/wnl.59.7.1105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12370476">Kondo et al. (2002)</a> identified homozygous mutations in the DAP12 gene (<a href="#0002">604142.0002</a>-<a href="#0003">604142.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12370476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Kaifu, T., Nakahara, J., Inui, M., Mishima, K., Momiyama, T., Kaji, M., Sugahara, A., Koito, H., Ujike-Asai, A., Nakamura, A., Kanazawa, K., Tan-Takeuchi, K., Iwasaki, K., Yokoyama, W. M., Kudo, A., Fujiwara, M., Asou, H., Takai, T. <strong>Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice.</strong> J. Clin. Invest. 111: 323-332, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12569157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12569157</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12569157[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/10.1172/JCI16923" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12569157">Kaifu et al. (2003)</a> noted that DAP12 is expressed in the monocyte-macrophage lineage, and that osteoclasts and microglial cells share a myeloid origin, providing a link between lesions in the brain and bone in patients with presenile dementia with bone cysts due to mutation in the DAP12 gene. In Dap12 -/- mice, <a href="#2" class="mim-tip-reference" title="Kaifu, T., Nakahara, J., Inui, M., Mishima, K., Momiyama, T., Kaji, M., Sugahara, A., Koito, H., Ujike-Asai, A., Nakamura, A., Kanazawa, K., Tan-Takeuchi, K., Iwasaki, K., Yokoyama, W. M., Kudo, A., Fujiwara, M., Asou, H., Takai, T. <strong>Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice.</strong> J. Clin. Invest. 111: 323-332, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12569157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12569157</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12569157[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/10.1172/JCI16923" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12569157">Kaifu et al. (2003)</a> found progressive osteopetrosis beginning at about 6 weeks of age. Bone marrow cells of Dap12 -/- mice failed to yield mature or functional osteoclasts in vitro. Brain sections from mutant mice showed hypomyelinosis, synaptic degeneration, and immature oligodendrocytes in the region of the thalamus. The Dap12 -/- mice showed a reduced startle reflex in response to acoustic stimuli and reduced prepulse inhibition, suggesting an impairment of sensorimotor gating. Northern blot analysis of brain tissue from wildtype mice detected Dap12 mRNA in oligodendrocytes and microglial cells, but not in astrocytes or neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12569157" 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="Koga, T., Inui, M., Inoue, K., Kim, S., Suematsu, A., Kobayashi, E., Iwata, T., Ohnishi, H., Matozaki, T., Kodama, T., Taniguchi, T., Takayanagi, H., Takai, T. <strong>Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis.</strong> Nature 428: 758-763, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15085135/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15085135</a>] [<a href="https://doi.org/10.1038/nature02444" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15085135">Koga et al. (2004)</a> showed that mice lacking immunoreceptor tyrosine-based activation motif (ITAM)-harboring adaptors Fc receptor common gamma subunit (<a href="/entry/147139">147139</a>) and DAP12 exhibit severe osteopetrosis owing to impaired osteoclast differentiation. In osteoclast precursor cells, Fc receptor-gamma and DAP12 associated with multiple immunoreceptors and activated calcium signaling through phospholipase C-gamma (see <a href="/entry/172420">172420</a>). Thus, ITAM-dependent costimulatory signals activated by multiple immunoreceptors are essential for the maintenance of bone homeostasis. <a href="#3" class="mim-tip-reference" title="Koga, T., Inui, M., Inoue, K., Kim, S., Suematsu, A., Kobayashi, E., Iwata, T., Ohnishi, H., Matozaki, T., Kodama, T., Taniguchi, T., Takayanagi, H., Takai, T. <strong>Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis.</strong> Nature 428: 758-763, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15085135/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15085135</a>] [<a href="https://doi.org/10.1038/nature02444" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15085135">Koga et al. (2004)</a> concluded that RANKL (<a href="/entry/602642">602642</a>) and macrophage colony-stimulating factor (<a href="/entry/120420">120420</a>) are not sufficient to activate the signals required for osteoclastogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15085135" 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="Hamerman, J. A., Tchao, N. K., Lowell, C. A., Lanier, L. L. <strong>Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12.</strong> Nature Immun. 6: 579-586, 2005. Note: Erratum: Nature Immun. 10: 223 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15895090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15895090</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15895090[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/ni1204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15895090">Hamerman et al. (2005)</a> found that macrophages from Dap12-deficient mice produced more Tnf (<a href="/entry/191160">191160</a>), Il6 (<a href="/entry/147620">147620</a>), and Il12b (<a href="/entry/161561">161561</a>) after stimulation of Toll-like receptors (TLRs; see <a href="/entry/603030">603030</a>) with various pathogen products than did macrophages from wildtype mice. Inflammatory cytokine production returned to wildtype levels after Dap12 reconstitution, but not after reconstitution with Dap12 lacking the ITAM. Macrophages lacking Syk, which signals downstream of Dap12, showed a phenotype identical to that of Dap12-deficient macrophages. Dap12-deficient mice produced Tnf at the same rate as wildtype mice but at higher levels in response to treatment with lipopolysaccharide combined with the Tnf-sensitizing agent D-galactosamine, and none survived endotoxic shock. Three days after infection with Listeria monocytogenes, Dap12-deficient mice had substantially fewer bacteria in spleen and liver compared with wildtype mice. <a href="#1" class="mim-tip-reference" title="Hamerman, J. A., Tchao, N. K., Lowell, C. A., Lanier, L. L. <strong>Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12.</strong> Nature Immun. 6: 579-586, 2005. Note: Erratum: Nature Immun. 10: 223 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15895090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15895090</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15895090[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/ni1204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15895090">Hamerman et al. (2005)</a> proposed that 1 or more DAP12-pairing receptors negatively regulate signaling through TLRs. They noted that Nasu-Hakola patients are not immunodeficient and, based on their findings, suggested that these patients may have enhanced resistance to certain pathogens. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15895090" 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 contrast to the findings of <a href="#1" class="mim-tip-reference" title="Hamerman, J. A., Tchao, N. K., Lowell, C. A., Lanier, L. L. <strong>Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12.</strong> Nature Immun. 6: 579-586, 2005. Note: Erratum: Nature Immun. 10: 223 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15895090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15895090</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15895090[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/ni1204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15895090">Hamerman et al. (2005)</a>, <a href="#10" class="mim-tip-reference" title="Turnbull, I. R., McDunn, J. E., Takai, T., Townsend, R. R., Cobb, J. P., Colonna, M. <strong>DAP12 (KARAP) amplifies inflammation and increases mortality from endotoxemia and septic peritonitis.</strong> J. Exp. Med. 202: 363-369, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16061725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16061725</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16061725[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/10.1084/jem.20050986" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16061725">Turnbull et al. (2005)</a> found that Dap12 -/- mice were less susceptible to septic shock induced by simple endotoxemia or cecal ligation and puncture than wildtype mice. They concluded that, during sepsis, DAP12 signaling augments the response to microbial products, amplifying inflammation and contributing to mortality. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16061725+15895090" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Turnbull, I. R., Gilfillan, S., Cella, M., Aoshi, T., Miller, M., Piccio, L., Hernandez, M., Colonna, M. <strong>Cutting edge: TREM-2 attenuates macrophage activation.</strong> J. Immun. 177: 3520-3524, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16951310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16951310</a>] [<a href="https://doi.org/10.4049/jimmunol.177.6.3520" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16951310">Turnbull et al. (2006)</a> found that mice lacking Trem2 were unable to inhibit cytokine production in response to microbial products. There was no difference in cytokine production by macrophages from Trem2-deficient mice and Dap12-deficient mice, leading <a href="#9" class="mim-tip-reference" title="Turnbull, I. R., Gilfillan, S., Cella, M., Aoshi, T., Miller, M., Piccio, L., Hernandez, M., Colonna, M. <strong>Cutting edge: TREM-2 attenuates macrophage activation.</strong> J. Immun. 177: 3520-3524, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16951310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16951310</a>] [<a href="https://doi.org/10.4049/jimmunol.177.6.3520" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16951310">Turnbull et al. (2006)</a> to conclude that Trem2 is the receptor operative in the increased macrophage cytokine production observed in Dap12-deficient cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16951310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=604142[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 POLYCYSTIC LIPOMEMBRANOUS OSTEODYSPLASIA WITH SCLEROSING LEUKOENCEPHALOPATHY 1</strong>
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<p>In all 26 Finnish patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL1; <a href="/entry/221770">221770</a>) as well as in 2 Swedish patients with known ancestors in Finland, <a href="#6" class="mim-tip-reference" title="Paloneva, J., Kestila, M., Wu, J., Salminen, A., Bohling, T., Ruotsalainen, V., Hakola, P., Bakker, A. B. H., Phillips, J. H., Pekkarinen, P., Lanier, L. L., Timonen, T., Peltonen, L. <strong>Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts.</strong> Nature Genet. 25: 357-361, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10888890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10888890</a>] [<a href="https://doi.org/10.1038/77153" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10888890">Paloneva et al. (2000)</a> found homozygosity for a genomic deletion of 5,265 bp, including 343 bp (exons 1-4 and 5-prime untranslated region) of the 604-bp transcribed region of the TYROBP gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10888890" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs386833840 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386833840;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs386833840?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs386833840" 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=rs386833840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a sequence analysis of the 342-bp coding region of the TYROBP gene from the genomic DNA of a Japanese patient with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL1; <a href="/entry/221770">221770</a>), <a href="#6" class="mim-tip-reference" title="Paloneva, J., Kestila, M., Wu, J., Salminen, A., Bohling, T., Ruotsalainen, V., Hakola, P., Bakker, A. B. H., Phillips, J. H., Pekkarinen, P., Lanier, L. L., Timonen, T., Peltonen, L. <strong>Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts.</strong> Nature Genet. 25: 357-361, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10888890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10888890</a>] [<a href="https://doi.org/10.1038/77153" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10888890">Paloneva et al. (2000)</a> found a homozygous 1-bp deletion in exon 3. The mutation created a frameshift in the open reading frame, predicting premature termination of the polypeptide chain after 52 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10888890" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated Japanese patients (patients NHD1, 5, and 6) with PLOSL1, <a href="#4" class="mim-tip-reference" title="Kondo, T., Takahashi, K., Kohara, N., Takahashi, Y., Hayashi, S., Takahashi, H., Matsuo, H., Yamazaki, M., Inoue, K., Miyamoto, K., Yamamura, T. <strong>Heterogeneity of presenile dementia with bone cysts (Nasu-Hakola disease): three genetic forms.</strong> Neurology 59: 1105-1107, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12370476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12370476</a>] [<a href="https://doi.org/10.1212/wnl.59.7.1105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12370476">Kondo et al. (2002)</a> identified homozygosity for the 1-bp deletion in exon 3 of the DAP12 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12370476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894732 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894732;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=rs104894732" 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=rs104894732" 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=RCV000006153" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006153" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006153</a>
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<p>In 2 unrelated Japanese patients (patients NHD3,4) with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL1; <a href="/entry/221770">221770</a>), both born to consanguineous parents, <a href="#4" class="mim-tip-reference" title="Kondo, T., Takahashi, K., Kohara, N., Takahashi, Y., Hayashi, S., Takahashi, H., Matsuo, H., Yamazaki, M., Inoue, K., Miyamoto, K., Yamamura, T. <strong>Heterogeneity of presenile dementia with bone cysts (Nasu-Hakola disease): three genetic forms.</strong> Neurology 59: 1105-1107, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12370476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12370476</a>] [<a href="https://doi.org/10.1212/wnl.59.7.1105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12370476">Kondo et al. (2002)</a> found a T-to-C transition in the second nucleotide of the DAP12 gene, changing the start codon from ATG (met) to ACG (thr). The patients had developed neuropsychiatric signs at age 30 to 35 years and both had x-ray signs of bone cysts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12370476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Hamerman2005" class="mim-anchor"></a>
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Hamerman, J. A., Tchao, N. K., Lowell, C. A., Lanier, L. L.
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<strong>Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15895090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15895090</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15895090[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=15895090" 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/ni1204" target="_blank">Full Text</a>]
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Kaifu, T., Nakahara, J., Inui, M., Mishima, K., Momiyama, T., Kaji, M., Sugahara, A., Koito, H., Ujike-Asai, A., Nakamura, A., Kanazawa, K., Tan-Takeuchi, K., Iwasaki, K., Yokoyama, W. M., Kudo, A., Fujiwara, M., Asou, H., Takai, T.
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<strong>Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12569157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12569157</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12569157[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=12569157" 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/10.1172/JCI16923" target="_blank">Full Text</a>]
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Koga, T., Inui, M., Inoue, K., Kim, S., Suematsu, A., Kobayashi, E., Iwata, T., Ohnishi, H., Matozaki, T., Kodama, T., Taniguchi, T., Takayanagi, H., Takai, T.
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<strong>Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis.</strong>
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Nature 428: 758-763, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15085135/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15085135</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15085135" 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/nature02444" target="_blank">Full Text</a>]
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Kondo, T., Takahashi, K., Kohara, N., Takahashi, Y., Hayashi, S., Takahashi, H., Matsuo, H., Yamazaki, M., Inoue, K., Miyamoto, K., Yamamura, T.
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<strong>Heterogeneity of presenile dementia with bone cysts (Nasu-Hakola disease): three genetic forms.</strong>
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Neurology 59: 1105-1107, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12370476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12370476</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12370476" 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/10.1212/wnl.59.7.1105" target="_blank">Full Text</a>]
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Lanier, L. L., Corliss, B. C., Wu, J., Leong, C., Phillips, J. H.
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<strong>Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells.</strong>
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Nature 391: 703-707, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9490415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9490415</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9490415" 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/10.1038/35642" target="_blank">Full Text</a>]
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Paloneva, J., Kestila, M., Wu, J., Salminen, A., Bohling, T., Ruotsalainen, V., Hakola, P., Bakker, A. B. H., Phillips, J. H., Pekkarinen, P., Lanier, L. L., Timonen, T., Peltonen, L.
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<strong>Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts.</strong>
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Nature Genet. 25: 357-361, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10888890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10888890</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10888890" 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/10.1038/77153" target="_blank">Full Text</a>]
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Paloneva, J., Mandelin, J., Kiialainen, A., Bohling, T., Prudlo, J., Hakola, P., Haltia, M., Konttinen, Y. T., Peltonen, L.
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<strong>DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features.</strong>
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J. Exp. Med. 198: 669-675, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12925681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12925681</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12925681[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=12925681" 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/10.1084/jem.20030027" target="_blank">Full Text</a>]
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Tomasello, E., Olcese, L., Vely, F., Geourgeon, C., Blery, M., Moqrich, A., Gautheret, D., Djabali, M., Mattei, M.-G., Vivier, E.
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<strong>Gene structure, expression pattern, and biological activity of mouse killer cell activating receptor-associated protein (KARAP)/DAP-12.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9852069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9852069</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9852069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.273.51.34115" target="_blank">Full Text</a>]
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Turnbull, I. R., Gilfillan, S., Cella, M., Aoshi, T., Miller, M., Piccio, L., Hernandez, M., Colonna, M.
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<strong>Cutting edge: TREM-2 attenuates macrophage activation.</strong>
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J. Immun. 177: 3520-3524, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16951310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16951310</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16951310" 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/10.4049/jimmunol.177.6.3520" target="_blank">Full Text</a>]
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Turnbull, I. R., McDunn, J. E., Takai, T., Townsend, R. R., Cobb, J. P., Colonna, M.
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<strong>DAP12 (KARAP) amplifies inflammation and increases mortality from endotoxemia and septic peritonitis.</strong>
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J. Exp. Med. 202: 363-369, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16061725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16061725</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16061725[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=16061725" 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/10.1084/jem.20050986" target="_blank">Full Text</a>]
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Paul J. Converse - updated : 3/13/2007
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Paul J. Converse - updated : 4/3/2006<br>Paul J. Converse - updated : 2/27/2006<br>Cassandra L. Kniffin - updated : 10/26/2004<br>Ada Hamosh - updated : 4/16/2004<br>Victor A. McKusick - updated : 12/27/2002<br>Victor A. McKusick - updated : 9/17/2002<br>Victor A. McKusick - updated : 6/22/2000
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carol : 11/16/2018<br>terry : 06/04/2012<br>mgross : 10/28/2010<br>terry : 10/25/2010<br>mgross : 3/13/2007<br>mgross : 4/6/2006<br>mgross : 4/6/2006<br>terry : 4/3/2006<br>mgross : 3/9/2006<br>terry : 2/27/2006<br>carol : 10/12/2005<br>tkritzer : 10/27/2004<br>ckniffin : 10/26/2004<br>alopez : 4/19/2004<br>terry : 4/16/2004<br>cwells : 1/2/2003<br>terry : 12/27/2002<br>alopez : 9/19/2002<br>carol : 9/17/2002<br>alopez : 8/7/2000<br>alopez : 6/23/2000<br>carol : 6/22/2000<br>joanna : 6/22/2000<br>mgross : 8/31/1999<br>mgross : 8/30/1999<br>psherman : 8/26/1999
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</span>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 604142
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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TYRO PROTEIN TYROSINE KINASE-BINDING PROTEIN; TYROBP
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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DNAX-ACTIVATION PROTEIN 12; DAP12
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TYROBP</em></strong>
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</span>
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</p>
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</div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 19q13.12
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:35,904,403-35,908,295 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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19q13.12
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</span>
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</td>
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<td>
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<span class="mim-font">
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Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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221770
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Natural killer (NK) cells express cell surface receptors that recognize major histocompatibility complex class I peptides (e.g., 142800) and inhibit NK cell-mediated cytotoxicity. NK cell receptors belong to 2 distinct groups: the immunoglobulin superfamily for the killer cell inhibitory receptors (KIRs; e.g., 602992), and the C-type lectin superfamily for the NKG2 receptors (e.g., 161555). These inhibitory receptors possess 'immunoreceptor tyrosine-based inhibitory motifs' (ITIMs) in their cytoplasmic domains that recruit SH2 domain-containing protein-tyrosine phosphatases, resulting in inactivation of NK cells. Certain isoforms of NK cell receptors lack ITIM sequences, and these non-inhibitory receptors activate, rather than inhibit, NK cells. Cell surface immunoglobulin receptors, T-cell antigen receptors (e.g., 186880), and certain Fc receptors noncovalently associate with small transmembrane proteins, such as CD3-delta (CD3D; 186790), -gamma (CD3G; 186740), -epsilon (CD3E; 186830), -zeta (CD3Z; 186780), CD79-alpha (112205), -beta (147245), and FCER1G (147139), that contain an 'immunoreceptor tyrosine-based activation motif' (ITAM) sequence and are required for signal transduction by these receptor complexes. Lanier et al. (1998) hypothesized that non-inhibitory NK cell receptors might require an associated protein with similar properties to mediate positive signal transduction. By searching an EST database with the protein sequences of CD3D, CD3G, CD3E, CD3Z, and FCER1G, they isolated a human CD1+ dendritic cell EST encoding an ITAM-containing protein, which they named DAP12. The predicted 113-amino acid DAP12 protein is composed of a signal peptide, a 14-amino acid extracellular domain, a transmembrane segment, and a 48-amino acid cytoplasmic domain. Although DAP12 shares less than 25% similarity with the human CD3D, CD3G, CD3E, CD3Z, and FCER1G proteins, its cytoplasmic domain contains a sequence that precisely corresponds to the prototype ITAM consensus. Potential sites for phosphorylation are also present in the DAP12 cytoplasmic region. The transmembrane domain of DAP12 contains the charged amino acid aspartic acid, which is conserved in the transmembrane domain of the CD3 subunits. </p><p>Tomasello et al. (1998) cloned the full-length coding sequence of mouse Tyrobp, which they called Karap for 'killer cell-activating receptor-associated protein.' The deduced human and mouse TYROBP proteins are 73% identical and are more similar to CD3Z and FCER1G than to other known ITAM-bearing molecules. RT-PCR analysis of a variety of hematopoietic and nonhematopoietic mouse cell lines revealed almost ubiquitous expression of Tyrobp. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lanier et al. (1998) demonstrated that the DAP12 protein is expressed on the cell surface as a disulfide-bonded homodimer. DAP12 noncovalently associated with KIR2DS2, a KIR family member that lacks an ITIM. Crosslinking of KIR2DS2/DAP12 complexes, but not of KIR2DS2 alone, resulted in cellular activation, as indicated by tyrosine phosphorylation of cellular proteins and upregulation of early-activation antigens. In addition, crosslinking of KIR2DS2/DAP12 complexes induced tyrosine phosphorylation of DAP12 and resulted in the association of phosphorylated DAP12 with the protein-tyrosine kinase SYK (600085). Peptides corresponding to the cytoplasmic domain of DAP12 formed complexes with the protein-tyrosine kinases SYK and ZAP70 (176947) only if the tyrosine residues in the ITAM of DAP12 were phosphorylated. Northern blot analysis detected an abundant 0.7-kb DAP12 transcript in human peripheral blood leukocytes and spleen but not in thymus or the other tissues examined. The authors found DAP12 expression in human NK cell lines but not in a T leukemia cell line or a B lymphoblastoid cell line. Lanier et al. (1998) suggested that DAP12 associates with the non-inhibitory isoforms of the KIR molecules in NK cells and permits cellular activation through these receptors, in a way similar to the function of the CD3 subunits in the T-cell receptor complex and the CD79 subunits in the B-cell receptor complex. </p><p>DAP12 associates with the cell surface receptor TREM2 (605086), and the DAP12-TREM2 complex is involved in dendritic cell maturation. Paloneva et al. (2003) analyzed differentiation of peripheral blood mononuclear cells from DAP12- and TREM2-deficient Finnish or German polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; 221770) patients into osteoclasts. They found that homozygous loss-of-function mutations in DAP12 or TREM2 resulted in inefficient, aberrant, and delayed differentiation into osteoclasts and significantly diminished bone resorption capability in vitro. RT-PCR analysis detected no differences between patient and control cells in the expression of several genes, but expression of DAP12 and TREM2 increased in control cells during osteoclastic differentiation. Paloneva et al. (2003) concluded that the DAP12-TREM2 signaling complex is important in the differentiation and function of osteoclasts. </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>Lanier et al. (1998) stated that the human TYROBP genomic sequence is contained within a cosmid (GenBank AD000833) that maps to 19q13.1. By FISH, Tomasello et al. (1998) mapped the mouse Tyrobp gene to 7B. They noted that human 19q13 shows homology of synteny with mouse chromosome 7. </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>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL1; 221770), also known as Nasu-Hakola disease, is a recessively inherited disorder characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. Identification of a shared 153-kb ancestor haplotype in all Finnish disease alleles on 19q13.1 was the first step in characterizing the molecular defect. The TYROBP gene was one of those located in the critical DNA region for PLOSL. Paloneva et al. (2000) failed to obtain products by PCR amplification of the coding region of TYROBP in the genomic DNA of Finnish PLOSL patients with primers flanking exons 1-4, whereas exon 5 was amplified normally. This indicated that the patients carried a homozygous deletion encompassing exons 1-4 of TYROBP (604142.0001). They located the 5-prime deletion breakpoint 2,900 bp upstream of the initiation methionine, and the 3-prime breakpoint in the last intron of TYROBP, 1,300 bp upstream of the termination codon. Sequence analysis of the 342-bp coding region of TYROBP from the genomic DNA of a Japanese PLOSL patient demonstrated homozygosity for a 1-bp deletion in exon 3 (604142.0002). This mutation created a frameshift in the open reading frame, predicting premature termination of the polypeptide chain after 52 amino acids. The mutation also changed the aspartic acid residue in the transmembrane domain that is essential in mediating the interaction between the TYROBP homodimer and the associated ligand-binding receptors on the surface of natural killer (NK) cells. On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class III molecules. No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP. In 1 Norwegian and 1 Swedish patient with the typical clinical features of PLOSL, linkage to 19q13.1 was excluded, and no sign of mutation of TYROBP was found in them or their families. </p><p>In 5 of 6 Japanese patients with PLOSL, Kondo et al. (2002) identified homozygous mutations in the DAP12 gene (604142.0002-604142.0003). </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>Animal Model</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Kaifu et al. (2003) noted that DAP12 is expressed in the monocyte-macrophage lineage, and that osteoclasts and microglial cells share a myeloid origin, providing a link between lesions in the brain and bone in patients with presenile dementia with bone cysts due to mutation in the DAP12 gene. In Dap12 -/- mice, Kaifu et al. (2003) found progressive osteopetrosis beginning at about 6 weeks of age. Bone marrow cells of Dap12 -/- mice failed to yield mature or functional osteoclasts in vitro. Brain sections from mutant mice showed hypomyelinosis, synaptic degeneration, and immature oligodendrocytes in the region of the thalamus. The Dap12 -/- mice showed a reduced startle reflex in response to acoustic stimuli and reduced prepulse inhibition, suggesting an impairment of sensorimotor gating. Northern blot analysis of brain tissue from wildtype mice detected Dap12 mRNA in oligodendrocytes and microglial cells, but not in astrocytes or neurons. </p><p>Koga et al. (2004) showed that mice lacking immunoreceptor tyrosine-based activation motif (ITAM)-harboring adaptors Fc receptor common gamma subunit (147139) and DAP12 exhibit severe osteopetrosis owing to impaired osteoclast differentiation. In osteoclast precursor cells, Fc receptor-gamma and DAP12 associated with multiple immunoreceptors and activated calcium signaling through phospholipase C-gamma (see 172420). Thus, ITAM-dependent costimulatory signals activated by multiple immunoreceptors are essential for the maintenance of bone homeostasis. Koga et al. (2004) concluded that RANKL (602642) and macrophage colony-stimulating factor (120420) are not sufficient to activate the signals required for osteoclastogenesis. </p><p>Hamerman et al. (2005) found that macrophages from Dap12-deficient mice produced more Tnf (191160), Il6 (147620), and Il12b (161561) after stimulation of Toll-like receptors (TLRs; see 603030) with various pathogen products than did macrophages from wildtype mice. Inflammatory cytokine production returned to wildtype levels after Dap12 reconstitution, but not after reconstitution with Dap12 lacking the ITAM. Macrophages lacking Syk, which signals downstream of Dap12, showed a phenotype identical to that of Dap12-deficient macrophages. Dap12-deficient mice produced Tnf at the same rate as wildtype mice but at higher levels in response to treatment with lipopolysaccharide combined with the Tnf-sensitizing agent D-galactosamine, and none survived endotoxic shock. Three days after infection with Listeria monocytogenes, Dap12-deficient mice had substantially fewer bacteria in spleen and liver compared with wildtype mice. Hamerman et al. (2005) proposed that 1 or more DAP12-pairing receptors negatively regulate signaling through TLRs. They noted that Nasu-Hakola patients are not immunodeficient and, based on their findings, suggested that these patients may have enhanced resistance to certain pathogens. </p><p>In contrast to the findings of Hamerman et al. (2005), Turnbull et al. (2005) found that Dap12 -/- mice were less susceptible to septic shock induced by simple endotoxemia or cecal ligation and puncture than wildtype mice. They concluded that, during sepsis, DAP12 signaling augments the response to microbial products, amplifying inflammation and contributing to mortality. </p><p>Turnbull et al. (2006) found that mice lacking Trem2 were unable to inhibit cytokine production in response to microbial products. There was no difference in cytokine production by macrophages from Trem2-deficient mice and Dap12-deficient mice, leading Turnbull et al. (2006) to conclude that Trem2 is the receptor operative in the increased macrophage cytokine production observed in Dap12-deficient cells. </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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<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>3 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 POLYCYSTIC LIPOMEMBRANOUS OSTEODYSPLASIA WITH SCLEROSING LEUKOENCEPHALOPATHY 1</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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TYROBP, EX1-4DEL
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<br />
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ClinVar: RCV000006151
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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 all 26 Finnish patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL1; 221770) as well as in 2 Swedish patients with known ancestors in Finland, Paloneva et al. (2000) found homozygosity for a genomic deletion of 5,265 bp, including 343 bp (exons 1-4 and 5-prime untranslated region) of the 604-bp transcribed region of the TYROBP gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 POLYCYSTIC LIPOMEMBRANOUS OSTEODYSPLASIA WITH SCLEROSING LEUKOENCEPHALOPATHY 1</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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TYROBP, 1-BP DEL, 141G
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<br />
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SNP: rs386833840,
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gnomAD: rs386833840,
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ClinVar: RCV000049808
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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 sequence analysis of the 342-bp coding region of the TYROBP gene from the genomic DNA of a Japanese patient with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL1; 221770), Paloneva et al. (2000) found a homozygous 1-bp deletion in exon 3. The mutation created a frameshift in the open reading frame, predicting premature termination of the polypeptide chain after 52 amino acids. </p><p>In 3 unrelated Japanese patients (patients NHD1, 5, and 6) with PLOSL1, Kondo et al. (2002) identified homozygosity for the 1-bp deletion in exon 3 of the DAP12 gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 POLYCYSTIC LIPOMEMBRANOUS OSTEODYSPLASIA WITH SCLEROSING LEUKOENCEPHALOPATHY 1</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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TYROBP, MET1THR
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<br />
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SNP: rs104894732,
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ClinVar: RCV000006153
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated Japanese patients (patients NHD3,4) with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL1; 221770), both born to consanguineous parents, Kondo et al. (2002) found a T-to-C transition in the second nucleotide of the DAP12 gene, changing the start codon from ATG (met) to ACG (thr). The patients had developed neuropsychiatric signs at age 30 to 35 years and both had x-ray signs of bone cysts. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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<p class="mim-text-font">
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Hamerman, J. A., Tchao, N. K., Lowell, C. A., Lanier, L. L.
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<strong>Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12.</strong>
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Nature Immun. 6: 579-586, 2005. Note: Erratum: Nature Immun. 10: 223 only, 2009.
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[PubMed: 15895090]
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[Full Text: https://doi.org/10.1038/ni1204]
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Kaifu, T., Nakahara, J., Inui, M., Mishima, K., Momiyama, T., Kaji, M., Sugahara, A., Koito, H., Ujike-Asai, A., Nakamura, A., Kanazawa, K., Tan-Takeuchi, K., Iwasaki, K., Yokoyama, W. M., Kudo, A., Fujiwara, M., Asou, H., Takai, T.
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<strong>Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice.</strong>
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J. Clin. Invest. 111: 323-332, 2003.
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[PubMed: 12569157]
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[Full Text: https://doi.org/10.1172/JCI16923]
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</li>
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<li>
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<p class="mim-text-font">
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Koga, T., Inui, M., Inoue, K., Kim, S., Suematsu, A., Kobayashi, E., Iwata, T., Ohnishi, H., Matozaki, T., Kodama, T., Taniguchi, T., Takayanagi, H., Takai, T.
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<strong>Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis.</strong>
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Nature 428: 758-763, 2004.
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[PubMed: 15085135]
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[Full Text: https://doi.org/10.1038/nature02444]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kondo, T., Takahashi, K., Kohara, N., Takahashi, Y., Hayashi, S., Takahashi, H., Matsuo, H., Yamazaki, M., Inoue, K., Miyamoto, K., Yamamura, T.
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<strong>Heterogeneity of presenile dementia with bone cysts (Nasu-Hakola disease): three genetic forms.</strong>
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Neurology 59: 1105-1107, 2002.
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[PubMed: 12370476]
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[Full Text: https://doi.org/10.1212/wnl.59.7.1105]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Lanier, L. L., Corliss, B. C., Wu, J., Leong, C., Phillips, J. H.
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<strong>Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells.</strong>
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Nature 391: 703-707, 1998.
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[PubMed: 9490415]
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[Full Text: https://doi.org/10.1038/35642]
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<p class="mim-text-font">
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Paloneva, J., Kestila, M., Wu, J., Salminen, A., Bohling, T., Ruotsalainen, V., Hakola, P., Bakker, A. B. H., Phillips, J. H., Pekkarinen, P., Lanier, L. L., Timonen, T., Peltonen, L.
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<strong>Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts.</strong>
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Nature Genet. 25: 357-361, 2000.
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[PubMed: 10888890]
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[Full Text: https://doi.org/10.1038/77153]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Paloneva, J., Mandelin, J., Kiialainen, A., Bohling, T., Prudlo, J., Hakola, P., Haltia, M., Konttinen, Y. T., Peltonen, L.
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<strong>DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features.</strong>
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J. Exp. Med. 198: 669-675, 2003.
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[PubMed: 12925681]
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[Full Text: https://doi.org/10.1084/jem.20030027]
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</p>
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<li>
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<p class="mim-text-font">
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Tomasello, E., Olcese, L., Vely, F., Geourgeon, C., Blery, M., Moqrich, A., Gautheret, D., Djabali, M., Mattei, M.-G., Vivier, E.
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<strong>Gene structure, expression pattern, and biological activity of mouse killer cell activating receptor-associated protein (KARAP)/DAP-12.</strong>
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J. Biol. Chem. 273: 34115-34119, 1998.
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[PubMed: 9852069]
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[Full Text: https://doi.org/10.1074/jbc.273.51.34115]
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Turnbull, I. R., Gilfillan, S., Cella, M., Aoshi, T., Miller, M., Piccio, L., Hernandez, M., Colonna, M.
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<strong>Cutting edge: TREM-2 attenuates macrophage activation.</strong>
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J. Immun. 177: 3520-3524, 2006.
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[PubMed: 16951310]
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[Full Text: https://doi.org/10.4049/jimmunol.177.6.3520]
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<p class="mim-text-font">
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Turnbull, I. R., McDunn, J. E., Takai, T., Townsend, R. R., Cobb, J. P., Colonna, M.
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<strong>DAP12 (KARAP) amplifies inflammation and increases mortality from endotoxemia and septic peritonitis.</strong>
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J. Exp. Med. 202: 363-369, 2005.
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[PubMed: 16061725]
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[Full Text: https://doi.org/10.1084/jem.20050986]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse - updated : 3/13/2007<br>Paul J. Converse - updated : 4/3/2006<br>Paul J. Converse - updated : 2/27/2006<br>Cassandra L. Kniffin - updated : 10/26/2004<br>Ada Hamosh - updated : 4/16/2004<br>Victor A. McKusick - updated : 12/27/2002<br>Victor A. McKusick - updated : 9/17/2002<br>Victor A. McKusick - updated : 6/22/2000
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Patti M. Sherman : 8/25/1999
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