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Entry
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- *176947 - ZETA-CHAIN-ASSOCIATED PROTEIN KINASE; ZAP70
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- OMIM
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<p>
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<span class="h4">*176947</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="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/176947">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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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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</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=ENSG00000115085;t=ENST00000264972" 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=7535" 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=176947" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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<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=ENSG00000115085;t=ENST00000264972" 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_001079,NM_001378594,NM_207519,XM_047445774,XM_047445775,XM_047445776,XR_007081582,XR_007081583" 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_001079" 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=176947" 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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<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=01495&isoform_id=01495_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/ZAP70" 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/1177044,24657846,26453340,31455611,31753147,46488944,62702261,119622323,119622324,194382468,1811715274,2217330834,2217330836,2217330839,2462496683,2462496685,2462496687,2462496690,2462496693,2462576903,2462576906,2462576908,2462576911,2462576914" 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/P43403" 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=7535" 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=ENSG00000115085;t=ENST00000264972" 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=ZAP70" 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=ZAP70" 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+7535" 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/ZAP70" 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:7535" 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/7535" 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=chr2&hgg_gene=ENST00000264972.10&hgg_start=97713576&hgg_end=97756364&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/genes/HGNC:12858" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="#mimMedlinePlusGeneticsFold" id="mimMedlinePlusGeneticsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Consumer-friendly information about the effects of genetic variation on human health."><span id="mimMedlinePlusGeneticsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>MedlinePlus Genetics</div>
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<div id="mimMedlinePlusGeneticsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://medlineplus.gov/genetics/condition/zap70-related-severe-combined-immunodeficiency" title="ZAP70-related severe combined immunodeficiency" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">ZAP70-related severe combi… </a></div><div style="margin-left: 0.5em;"><a href="https://medlineplus.gov/genetics/gene/zap70" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">ZAP70 gene </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=176947[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=176947[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/ENSG00000115085" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=ZAP70" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=ZAP70" 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=ZAP70" 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="http://structure.bmc.lu.se/idbase/ZAP70base/index.php" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ZAP70&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/PA37447" 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:12858" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0015295.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:99613" 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/ZAP70#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:99613" 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/7535/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=7535" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00016416;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-050522-257" 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:7535" 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=ZAP70&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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176947
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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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ZETA-CHAIN-ASSOCIATED PROTEIN KINASE; ZAP70
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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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SYK-RELATED TYROSINE KINASE; SRK<br />
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PROTEIN TYROSINE KINASE ZAP70<br />
|
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ZETA-ASSOCIATED PROTEIN, 70-KD
|
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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=ZAP70" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ZAP70</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/2/491?start=-3&limit=10&highlight=491">2q11.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:97713576-97756364&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'})">2:97,713,576-97,756,364</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
|
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Location
|
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</th>
|
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<th>
|
|
Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=617006,269840" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
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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>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/2/491?start=-3&limit=10&highlight=491">
|
|
2q11.2
|
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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">
|
|
Autoimmune disease, multisystem, infantile-onset, 2
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/617006"> 617006 </a>
|
|
|
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</span>
|
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</td>
|
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<td>
|
|
<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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<tr>
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<td>
|
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<span class="mim-font">
|
|
Immunodeficiency 48
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/269840"> 269840 </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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<p>The ZAP70 gene encodes a tyrosine kinase that is a critical T-cell signaling molecule that interacts with the zeta-chain (CD247; <a href="/entry/186780">186780</a>) of the T-cell receptor (TCR). It is expressed predominantly in T and NK cells (summary by <a href="#4" class="mim-tip-reference" title="Chan, A. Y., Punwani, D., Kadlecek, T. A., Cowan, M. J., Olson, J. L., Mathes, E. F., Sunderam, U., Fu, S. M., Srinivasan, R., Kuriyan, J., Brenner, S. E., Weiss, A., Puck, J. M. <strong>A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70.</strong> J. Exp. Med. 213: 155-165, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26783323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26783323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26783323[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.20150888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26783323">Chan et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26783323" 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="Chan, A. C., Iwashima, M., Turck, C. W., Weiss, A. <strong>ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain.</strong> Cell 71: 649-662, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1423621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1423621</a>] [<a href="https://doi.org/10.1016/0092-8674(92)90598-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1423621">Chan et al. (1992)</a> isolated a cDNA encoding a 70-kD tyrosine phosphoprotein, ZAP70, that associates with the zeta chain and undergoes tyrosine phosphorylation following TCR stimulation. The ZAP70 gene is expressed in T- and natural killer cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1423621" 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="#3" class="mim-tip-reference" title="Chan, A. C., Kadlecek, T. A., Elder, M. E., Filipovich, A. H., Kuo, W.-L., Iwashima, M., Parslow, T. G., Weiss, A. <strong>ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency.</strong> Science 264: 1599-1601, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8202713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8202713</a>] [<a href="https://doi.org/10.1126/science.8202713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8202713">Chan et al. (1994)</a> mapped the ZAP70 gene to chromosome 2q12 by hybridization of a genomic fragment to human/rodent somatic hybrid cell DNA and by fluorescence in situ hybridization (FISH). <a href="#9" class="mim-tip-reference" title="Ku, G., Malissen, B., Mattei, M.-G. <strong>Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans.</strong> Immunogenetics 40: 300-302, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8082894/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8082894</a>] [<a href="https://doi.org/10.1007/BF00189976" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8082894">Ku et al. (1994)</a> likewise assigned the ZAP70 gene to 2q12 by isotopic in situ hybridization. They mapped the murine homolog to mouse chromosome 1 by the same method. <a href="#12" class="mim-tip-reference" title="Saito, T., Matsuda, Y., Ito, H., Fusaki, N., Hori, T., Yamamoto, T. <strong>Localization of Zap70, the gene for a T cell-specific protein tyrosine kinase, to mouse and rat chromosomes by fluorescence in situ hybridization and molecular genetic linkage analyses.</strong> Mammalian Genome 8: 45-46, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9021148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9021148</a>] [<a href="https://doi.org/10.1007/s003359900345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9021148">Saito et al. (1997)</a> also mapped the gene to mouse chromosome 1 and rat chromosome 9q22.1 by FISH; by genetic linkage analysis, they further refined the location of the gene on mouse chromosome 1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8082894+8202713+9021148" 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="#16" class="mim-tip-reference" title="Watts, J. D., Brabb, T., Bures, E. J., Wange, R. L., Samelson, L. E., Aebersold, R. <strong>Identification and characterization of a substrate specific for the T cell protein tyrosine kinase ZAP-70.</strong> FEBS Lett. 398: 217-222, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8977110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8977110</a>] [<a href="https://doi.org/10.1016/s0014-5793(96)01241-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8977110">Watts et al. (1996)</a> identified a ZAP70 phosphorylation site on the erythrocyte band-3 protein (see <a href="/entry/109270">109270</a>) cytoplasmic fragment. They found that this phosphorylation site is distinct from the phosphorylation sites for other PTKs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8977110" 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>Animals deficient in pre-TCR-alpha have few alpha-beta lineage cells but an increased number of gamma-delta T cells. These gamma-delta T cells exhibit more extensive TCR-beta rearrangement than gamma-delta T cells from wildtype mice. These observations are consistent with the idea that different signals emanating from the gamma-delta-TCR and pre-TCR instruct lineage commitment. Using confocal microscopy and biochemistry to analyze the initiation of signaling, <a href="#11" class="mim-tip-reference" title="Saint-Ruf, C., Panigada, M., Azogui, O., Debey, P., von Boehmer, H., Grassi, F. <strong>Different initiation of pre-TCR and gamma-delta-TCR signalling.</strong> Nature 406: 524-527, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10952314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10952314</a>] [<a href="https://doi.org/10.1038/35020093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10952314">Saint-Ruf et al. (2000)</a> showed that the pre-TCR, but not the gamma-delta TCR, colocalizes with the p56(lck) Src kinase (<a href="/entry/153390">153390</a>) into glycolipid-enriched membrane domains (rafts) apparently without any need for ligation. This results in the phosphorylation of CD3-epsilon (<a href="/entry/186830">186830</a>) and ZAP70 signal transducing molecules. <a href="#11" class="mim-tip-reference" title="Saint-Ruf, C., Panigada, M., Azogui, O., Debey, P., von Boehmer, H., Grassi, F. <strong>Different initiation of pre-TCR and gamma-delta-TCR signalling.</strong> Nature 406: 524-527, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10952314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10952314</a>] [<a href="https://doi.org/10.1038/35020093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10952314">Saint-Ruf et al. (2000)</a> stated that their results indicated clear differences between pre-TCR and gamma-delta-TCR signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10952314" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Colucci, F., Schweighoffer, E., Tomasello, E., Turner, M., Ortaldo, J. R., Vivier, E., Tybulewicz, V. L. J., Di Santo, J. P. <strong>Natural cytotoxicity uncoupled from the Syk and ZAP-70 intracellular kinases.</strong> Nature Immun. 3: 288-294, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11836527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11836527</a>] [<a href="https://doi.org/10.1038/ni764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11836527">Colucci et al. (2002)</a> noted that humans with mutations in ZAP70 have T-cell immunodeficiency, that mice lacking Zap70 have blocked T-cell development, and that mice lacking Syk (<a href="/entry/600085">600085</a>) have a failure of B-cell development. NK cells express both molecules, which associate with immunoreceptor tyrosine-based activation motifs (ITAMs). Using mice deficient in both Zap70 and Syk, <a href="#5" class="mim-tip-reference" title="Colucci, F., Schweighoffer, E., Tomasello, E., Turner, M., Ortaldo, J. R., Vivier, E., Tybulewicz, V. L. J., Di Santo, J. P. <strong>Natural cytotoxicity uncoupled from the Syk and ZAP-70 intracellular kinases.</strong> Nature Immun. 3: 288-294, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11836527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11836527</a>] [<a href="https://doi.org/10.1038/ni764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11836527">Colucci et al. (2002)</a> observed NK cell activity comparable to that in wildtype mice. The mutant cells expressed Nkg2d (<a href="/entry/602893">602893</a>) and were able to lyse targets with and without Nkg2d ligands in vitro and in vivo. However, wildtype cells, but not the double-deficient cells, responded to CD16 (<a href="/entry/146740">146740</a>) and Ly49d (see <a href="/entry/604274">604274</a>) cross-linking with increased cytotoxicity, suggesting that these 2 ITAM-bearing receptors are unable to signal in the mutant cells. Inhibitors of PI3K (see <a href="/entry/601232">601232</a>) or Src kinases blocked and, in combination, abrogated cytotoxic activity in the mutant cells, whereas inhibition of both kinases was required to reduce wildtype NK activity. <a href="#5" class="mim-tip-reference" title="Colucci, F., Schweighoffer, E., Tomasello, E., Turner, M., Ortaldo, J. R., Vivier, E., Tybulewicz, V. L. J., Di Santo, J. P. <strong>Natural cytotoxicity uncoupled from the Syk and ZAP-70 intracellular kinases.</strong> Nature Immun. 3: 288-294, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11836527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11836527</a>] [<a href="https://doi.org/10.1038/ni764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11836527">Colucci et al. (2002)</a> concluded that intracellular signaling in the adaptive immune system, i.e., in B and T cells, is fundamentally different from that in the NK cells of the innate immune system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11836527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Sasahara, Y., Rachid, R., Byrne, M. J., de la Fuente, M. A., Abraham, R. T., Ramesh, N., Geha, R. S. <strong>Mechanism of recruitment of WASP to the immunological synapse and of its activation following TCR ligation.</strong> Molec. Cell 10: 1269-1281, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12504004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12504004</a>] [<a href="https://doi.org/10.1016/s1097-2765(02)00728-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12504004">Sasahara et al. (2002)</a> showed that the adaptor protein CRKL (<a href="/entry/602007">602007</a>) binds directly to WIP (<a href="/entry/602357">602357</a>) and that, following T-cell receptor ligation, a CRKL-WIP-WASP (<a href="/entry/300392">300392</a>) complex is recruited by ZAP70 to lipid rafts and immunologic synapses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12504004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Crespo, M., Bosch, F., Villamor, N., Bellosillo, B., Colomer, D., Rozman, M., Marce, S., Lopez-Guillermo, A., Campo, E., Montserrat, E. <strong>ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia.</strong> New Eng. J. Med. 348: 1764-1775, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12724482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12724482</a>] [<a href="https://doi.org/10.1056/NEJMoa023143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12724482">Crespo et al. (2003)</a> found that ZAP70 expression by cells in chronic lymphocytic leukemia (CLL; <a href="/entry/151400">151400</a>), as ascertained by flow cytometric analysis, is a simple and reliable surrogate for the identification of immunoglobulin heavy chain variable region gene (IGHV; see <a href="/entry/147070">147070</a>) mutations. Moreover, ZAP70 expression by itself can be used as a prognostic marker. For these reasons, they urged that ZAP70 analysis be included in the workup of patients with CLL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12724482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using in vitro binding assays, <a href="#8" class="mim-tip-reference" title="Gu, Y., Chae, H.-D., Siefring, J. E., Jasti, A. C., Hildeman, D. A., Williams, D. A. <strong>RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development.</strong> Nature Immun. 7: 1182-1190, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17028588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17028588</a>] [<a href="https://doi.org/10.1038/ni1396" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17028588">Gu et al. (2006)</a> showed that Rhoh (<a href="/entry/602037">602037</a>) interacted with Zap70. The Rhoh-Zap70 interaction depended mainly on conserved tyrosine-phosphorylated ITAMs in Rhoh and the SH2 domains in Zap70. Rhoh was required for proper recruitment of Zap70 to plasma membrane and cytoskeleton fractions in thymocytes and consequently for activation of Zap70 in TCR signal transduction. Based on these findings and studies in Rhoh -/- mice, <a href="#8" class="mim-tip-reference" title="Gu, Y., Chae, H.-D., Siefring, J. E., Jasti, A. C., Hildeman, D. A., Williams, D. A. <strong>RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development.</strong> Nature Immun. 7: 1182-1190, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17028588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17028588</a>] [<a href="https://doi.org/10.1038/ni1396" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17028588">Gu et al. (2006)</a> concluded that RHOH is a critical regulator of thymocyte development and TCR signaling via its recruitment and activation of ZAP70. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17028588" 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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In 3 affected females from 2 Mennonite families with immunodeficiency-48 (IMD48; <a href="/entry/269840">269840</a>) characterized by a selective T-cell defect, <a href="#1" class="mim-tip-reference" title="Arpaia, E., Shahar, M., Dadi, H., Cohen, A., Roifman, C. M. <strong>Defective T cell receptor signaling and CD8(+) thymic selection in humans lacking Zap-70 kinase.</strong> Cell 76: 947-958, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8124727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8124727</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90368-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8124727">Arpaia et al. (1994)</a> identified a homozygous mutation in the ZAP70 (<a href="#0001">176947.0001</a>), resulting in loss of the activity of this kinase. The mutation was present in heterozygous state in the parents and 3 unaffected sibs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8124727" 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 sibs, 2 boys and a girl, with IMD48, <a href="#3" class="mim-tip-reference" title="Chan, A. C., Kadlecek, T. A., Elder, M. E., Filipovich, A. H., Kuo, W.-L., Iwashima, M., Parslow, T. G., Weiss, A. <strong>ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency.</strong> Science 264: 1599-1601, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8202713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8202713</a>] [<a href="https://doi.org/10.1126/science.8202713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8202713">Chan et al. (1994)</a> identified compound heterozygous mutations in the ZAP70 gene (<a href="#0002">176947.0002</a> and <a href="#0003">176947.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8202713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a female infant with IMD48, <a href="#7" class="mim-tip-reference" title="Elder, M. E., Lin, D., Clever, J., Chan, A. C., Hope, T. J., Weiss, A., Parslow, T. G. <strong>Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase.</strong> Science 264: 1596-1599, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8202712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8202712</a>] [<a href="https://doi.org/10.1126/science.8202712" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8202712">Elder et al. (1994)</a> identified a homozygous mutation in the ZAP70 gene (<a href="#0004">176947.0004</a>). The parents and unaffected sibs were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8202712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Chronic Lymphocytic Leukemia</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Rassenti, L. Z., Huynh, L., Toy, T. L., Chen, L., Keating, M. J., Gribben, J. G., Neuberg, D. S., Flinn, I. W., Rai, K. R., Byrd, J. C., Kay, N. E., Greaves, A., Weiss, A., Kipps, T. J. <strong>ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia.</strong> New Eng. J. Med. 351: 893-901, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15329427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15329427</a>] [<a href="https://doi.org/10.1056/NEJMoa040857" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15329427">Rassenti et al. (2004)</a> noted that in cases of aggressive chronic lymphocytic leukemia (<a href="/entry/151400">151400</a>), CLL cells usually express an unmutated immunoglobulin heavy chain variable region gene (IGHV; see <a href="/entry/147070">147070</a>) and ZAP70 gene, whereas in cases of indolent disease, CLL cells usually express a mutated immunoglobulin heavy chain variable region gene but lack expression of ZAP70. In studies of 307 patients with CLL, <a href="#10" class="mim-tip-reference" title="Rassenti, L. Z., Huynh, L., Toy, T. L., Chen, L., Keating, M. J., Gribben, J. G., Neuberg, D. S., Flinn, I. W., Rai, K. R., Byrd, J. C., Kay, N. E., Greaves, A., Weiss, A., Kipps, T. J. <strong>ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia.</strong> New Eng. J. Med. 351: 893-901, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15329427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15329427</a>] [<a href="https://doi.org/10.1056/NEJMoa040857" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15329427">Rassenti et al. (2004)</a> found that although the presence of an unmutated immunoglobulin heavy chain variable region gene was strongly associated with expression of ZAP70, ZAP70 was a stronger predictor of the need for treatment in B-cell CLL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15329427" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Infantile-Onset Multisystem Autoimmune Disease 2</em></strong></p><p>
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In 2 sibs with infantile-onset multisystem autoimmune disease-2 (ADMIO2; <a href="/entry/617006">617006</a>), <a href="#4" class="mim-tip-reference" title="Chan, A. Y., Punwani, D., Kadlecek, T. A., Cowan, M. J., Olson, J. L., Mathes, E. F., Sunderam, U., Fu, S. M., Srinivasan, R., Kuriyan, J., Brenner, S. E., Weiss, A., Puck, J. M. <strong>A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70.</strong> J. Exp. Med. 213: 155-165, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26783323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26783323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26783323[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.20150888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26783323">Chan et al. (2016)</a> identified compound heterozygous missense mutations in the ZAP70 gene (R192W, <a href="#0006">176947.0006</a> and R360P, <a href="#0007">176947.0007</a>). The mutations were found by whole-exome sequencing and segregated with the disorder in the family. Studies of transfected cell lines and cells from the carrier parents showed that the R192W was a hypomorphic allele with reduced binding to phosphorylated zeta-chain (CD247; <a href="/entry/186780">186780</a>) of the TCR, whereas R360P was weakly hyperactive compared to wildtype, most likely due to disruption of the autoinhibitory mechanism. The combination of hypomorphic and activating mutations suggested a novel disease mechanism resulting in a theretofore undescribed human ZAP70-associated autoimmune disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26783323" 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="#13" class="mim-tip-reference" title="Sakaguchi, N., Takahashi, T., Hata, H., Nomura, T., Tagami, T., Yamazaki, S., Sakihama, T., Matsutani, T., Negishi, I., Nakatsuru, S., Sakaguchi, S. <strong>Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice.</strong> Nature 426: 454-460, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14647385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14647385</a>] [<a href="https://doi.org/10.1038/nature02119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14647385">Sakaguchi et al. (2003)</a> reported that the SKG strain, which is derived from a closed breeding colony of BALB/c mice, spontaneously develops chronic arthritis. Joint swelling with hyperemia became macroscopically evident in SKG mice at about 2 months of age, initially at a few interphalangeal joints of the forepaws, then progressing in a symmetrical fashion to swelling of the other finger joints of the forepaws and hindpaws and larger joints (wrists and ankles). Knee, elbow, shoulder, or vertebral joints were rarely affected except for the joint at the base of the tail in aged SKG mice. Radiographic examination revealed destruction and fusion of the subchondral bones, joint dislocation, and osteoporosis by 8 to 12 months of age. Despite suffering from such severe chronic arthritis, most SKG mice survived well to 1 year of age, generally with more severe arthritides in females. <a href="#13" class="mim-tip-reference" title="Sakaguchi, N., Takahashi, T., Hata, H., Nomura, T., Tagami, T., Yamazaki, S., Sakihama, T., Matsutani, T., Negishi, I., Nakatsuru, S., Sakaguchi, S. <strong>Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice.</strong> Nature 426: 454-460, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14647385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14647385</a>] [<a href="https://doi.org/10.1038/nature02119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14647385">Sakaguchi et al. (2003)</a> found that this arthritis is an autosomal recessive trait. They found a tryptophan-to-cysteine substitution at residue 163 (W163C) at the start of the second SH2 domain of ZAP70. Altered signal transduction from T-cell antigen receptor (see <a href="/entry/186740">186740</a>) through the aberrant ZAP70 changes the threshold of T cells to thymic selection, leading to the positive selection of otherwise negatively selected autoimmune T cells. <a href="#13" class="mim-tip-reference" title="Sakaguchi, N., Takahashi, T., Hata, H., Nomura, T., Tagami, T., Yamazaki, S., Sakihama, T., Matsutani, T., Negishi, I., Nakatsuru, S., Sakaguchi, S. <strong>Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice.</strong> Nature 426: 454-460, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14647385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14647385</a>] [<a href="https://doi.org/10.1038/nature02119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14647385">Sakaguchi et al. (2003)</a> speculated that thymic production of arthritogenic T cells due to a genetically determined selection shift of the T-cell repertoire towards high self-reactivity might be crucial to the development of disease in a subset of patients with rheumatoid arthritis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14647385" 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> rs730880318 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs730880318;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/rs730880318?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=rs730880318" 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=rs730880318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 females in 2 different families from a genetically isolated Mennonite community in Ontario, <a href="#1" class="mim-tip-reference" title="Arpaia, E., Shahar, M., Dadi, H., Cohen, A., Roifman, C. M. <strong>Defective T cell receptor signaling and CD8(+) thymic selection in humans lacking Zap-70 kinase.</strong> Cell 76: 947-958, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8124727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8124727</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90368-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8124727">Arpaia et al. (1994)</a> demonstrated that immunodeficiency-48 (IMD48; <a href="/entry/269840">269840</a>) due to a selective T-cell defect was the result of homozygosity for a splice mutation in the ZAP70 gene. An intronic point mutation created a new splice acceptor site with the insertion of 9 nucleotides in the mRNA and 3 additional amino acids in the protein product. The G-to-A transition at position -11 from the 3-prime end of the intron created an AluI restriction site which <a href="#1" class="mim-tip-reference" title="Arpaia, E., Shahar, M., Dadi, H., Cohen, A., Roifman, C. M. <strong>Defective T cell receptor signaling and CD8(+) thymic selection in humans lacking Zap-70 kinase.</strong> Cell 76: 947-958, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8124727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8124727</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90368-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8124727">Arpaia et al. (1994)</a> used for identifying heterozygotes in the family. Both parents were carriers and 3 of 4 sibs were heterozygous as well. The mutation resulted in an unstable protein that could not be detected by Western blotting or kinase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8124727" 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=RCV000014158 OR RCV000726208 OR RCV001851845 OR RCV003390681" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014158, RCV000726208, RCV001851845, RCV003390681" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014158...</a>
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<p>In 2 brothers and a sister with immunodeficiency-48 (IMD48; <a href="/entry/269840">269840</a>), <a href="#3" class="mim-tip-reference" title="Chan, A. C., Kadlecek, T. A., Elder, M. E., Filipovich, A. H., Kuo, W.-L., Iwashima, M., Parslow, T. G., Weiss, A. <strong>ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency.</strong> Science 264: 1599-1601, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8202713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8202713</a>] [<a href="https://doi.org/10.1126/science.8202713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8202713">Chan et al. (1994)</a> identified compound heterozygous mutations in the ZAP70 gene. One mutation, inherited from the mother, was a 9-bp insertion due to a G-to-A transition within an intron 9-bp upstream of the normal splice acceptor site. The mutation resulted in a more favored splice acceptor site (AGC rather than AGA) and in the addition of 3 amino acids, leu-glu-gln, within the catalytic domain of the ZAP70 protein. The other mutation, inherited from the father, was a 1763C-A transition resulting in a ser518-to-arg (S518R; <a href="#0003">176947.0003</a>) substitution. Ser518 is in a highly conserved region of the catalytic domain of the ZAP70 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8202713" 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">rs104893674 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893674;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=rs104893674" 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=rs104893674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the ser518-to-arg (S518R) mutation in the ZAP70 gene that was found in compound heterozygous state in patients with immunodeficiency-48 (IMD48; <a href="/entry/269840">269840</a>) by <a href="#3" class="mim-tip-reference" title="Chan, A. C., Kadlecek, T. A., Elder, M. E., Filipovich, A. H., Kuo, W.-L., Iwashima, M., Parslow, T. G., Weiss, A. <strong>ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency.</strong> Science 264: 1599-1601, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8202713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8202713</a>] [<a href="https://doi.org/10.1126/science.8202713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8202713">Chan et al. (1994)</a>, see <a href="#0002">176947.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8202713" 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">rs730880319 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs730880319;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=rs730880319" 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=rs730880319" 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=RCV000014164 OR RCV005089250" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014164, RCV005089250" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014164...</a>
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<p>In a 1-year-old female with immunodeficiency-48 (IMD48; <a href="/entry/269840">269840</a>), <a href="#7" class="mim-tip-reference" title="Elder, M. E., Lin, D., Clever, J., Chan, A. C., Hope, T. J., Weiss, A., Parslow, T. G. <strong>Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase.</strong> Science 264: 1596-1599, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8202712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8202712</a>] [<a href="https://doi.org/10.1126/science.8202712" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8202712">Elder et al. (1994)</a> demonstrated homozygosity for a 13-bp deletion involving nucleotides 1719-1731 (1719_1931del13) of the ZAP70 gene. The deletion would be expected to cause a translational frameshift after amino acid 503, resulting in premature termination 35 codons downstream and yielding a mutant protein 82 residues shorter than the wildtype. Both parents and 2 unaffected sibs were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8202712" 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> rs137853201 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853201;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/rs137853201?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=rs137853201" 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=rs137853201" 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=RCV000033214 OR RCV001305022" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033214, RCV001305022" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033214...</a>
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<p>In an 8-month-old girl with immunodeficiency-48 (IMD48; <a href="/entry/269840">269840</a>), <a href="#15" class="mim-tip-reference" title="Toyabe, S.-I., Watanabe, A., Harada, W., Karasawa, T., Uchiyama, M. <strong>Specific immunoglobulin E responses in ZAP-70-deficient patients are mediated by Syk-dependent T-cell receptor signalling.</strong> Immunology 103: 164-171, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11412303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11412303</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11412303[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/10.1046/j.1365-2567.2001.01246.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11412303">Toyabe et al. (2001)</a> detected a homozygous 1603G-A transition in the ZAP70 gene, resulting in an arg465-to-his substitution in the kinase domain. The patient lacked CD8-positive T cells but had normal CD4-positive T cells and serum Ig levels. ZAP70-deficient patients rarely have antigen-specific antibodies, but this patient developed specific IgE antibodies (see <a href="/entry/147050">147050</a>) to food allergens without developing food allergies. Stimulation of peripheral blood mononuclear cells with phorbol myristate acetate, but not with other mitogens, resulted in production of high levels of IL4 (<a href="/entry/147780">147780</a>), T-cell expression of CD40L (<a href="/entry/300386">300386</a>), and expression of germline and mature IgE epsilon transcripts in B cells. Western blot analysis showed expression of high levels of SYK (<a href="/entry/600085">600085</a>) in T cells from the patient, which also expressed high levels of CD40L, but not in those from controls. A protein tyrosine kinase/SYK inhibitor aborted IL4 production and CD40L expression. <a href="#15" class="mim-tip-reference" title="Toyabe, S.-I., Watanabe, A., Harada, W., Karasawa, T., Uchiyama, M. <strong>Specific immunoglobulin E responses in ZAP-70-deficient patients are mediated by Syk-dependent T-cell receptor signalling.</strong> Immunology 103: 164-171, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11412303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11412303</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11412303[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/10.1046/j.1365-2567.2001.01246.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11412303">Toyabe et al. (2001)</a> proposed that partial T-cell function and a T-cell receptor-signaling pathway can be retained in some ZAP70-deficient patients via SYK. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11412303" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 2 (1 family)</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs199840952 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199840952;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/rs199840952?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=rs199840952" 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=rs199840952" 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=RCV000208562 OR RCV000227350 OR RCV001559120 OR RCV001853323" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000208562, RCV000227350, RCV001559120, RCV001853323" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000208562...</a>
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<p>In 2 sibs with infantile-onset multisystem autoimmune disease-2 (ADMIO2; <a href="/entry/617006">617006</a>), <a href="#4" class="mim-tip-reference" title="Chan, A. Y., Punwani, D., Kadlecek, T. A., Cowan, M. J., Olson, J. L., Mathes, E. F., Sunderam, U., Fu, S. M., Srinivasan, R., Kuriyan, J., Brenner, S. E., Weiss, A., Puck, J. M. <strong>A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70.</strong> J. Exp. Med. 213: 155-165, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26783323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26783323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26783323[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.20150888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26783323">Chan et al. (2016)</a> identified compound heterozygous mutations in the ZAP70 gene: a c.574C-T transition (c.574C-T, NM_001079.3) in exon 5, resulting in an arg192-to-trp (R192W) substitution in the phosphotyrosine-binding pocket, and a c.1079G-C transversion in exon 9, resulting in an arg360-to-pro (R360P; <a href="#0007">176947.0007</a>) substitution in the N-lobe of the kinase domain. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Transfection of the mutations into HEK293 T cells showed that the R192W mutant had reduced association with phosphorylated zeta-chains, consistent with it being a hypomorphic allele. Transfection of the R360P mutant did not result in constitutive LAT phosphorylation, but nearby D327P and K362E mutants did cause increased activity, suggesting that all these mutations may interfere with proper autoinhibition of ZAP70. Further studies in another T-cell line indicated that the R360P mutant is weakly hyperactive due to disruption of its autoinhibitory mechanism. Patient cells were not available because both patients had undergone hematopoietic stem cell transplantation, but studies of cells from the heterozygous parents were consistent with R192W being a hypoactive mutant and R360P being weakly hyperactive. Finally, double-transfected cells showed that the R360P phenotype was masked by wildtype ZAP70 and revealed only in the presence of the hypoactive R192W allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26783323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 2 (1 family)</strong>
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ZAP70, ARG360PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs869025224 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869025224;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=rs869025224" 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=rs869025224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000208547 OR RCV000233631 OR RCV001559121" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000208547, RCV000233631, RCV001559121" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000208547...</a>
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<p>For discussion of the c.1079G-C transversion (c.1079G-C, NM_001079.3) in exon 9 of the ZAP70 gene, resulting in an arg360-to-pro (R360P) substitution, that was found in compound heterozygous state in 2 sibs with infantile-onset multisystem autoimmune disease-2 (ADMIO2; <a href="/entry/617006">617006</a>) by <a href="#4" class="mim-tip-reference" title="Chan, A. Y., Punwani, D., Kadlecek, T. A., Cowan, M. J., Olson, J. L., Mathes, E. F., Sunderam, U., Fu, S. M., Srinivasan, R., Kuriyan, J., Brenner, S. E., Weiss, A., Puck, J. M. <strong>A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70.</strong> J. Exp. Med. 213: 155-165, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26783323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26783323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26783323[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.20150888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26783323">Chan et al. (2016)</a>, see <a href="#0006">176947.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26783323" 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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<br />
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<a id="references"class="mim-anchor"></a>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<p class="mim-text-font">
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[<a href="https://doi.org/10.1016/0092-8674(94)90368-9" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
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<a id="Chan1992" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1423621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1423621</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1423621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0092-8674(92)90598-7" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
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<a id="Chan1994" class="mim-anchor"></a>
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<div class="">
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Chan, A. C., Kadlecek, T. A., Elder, M. E., Filipovich, A. H., Kuo, W.-L., Iwashima, M., Parslow, T. G., Weiss, A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8202713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8202713</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8202713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.8202713" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Chan2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Chan, A. Y., Punwani, D., Kadlecek, T. A., Cowan, M. J., Olson, J. L., Mathes, E. F., Sunderam, U., Fu, S. M., Srinivasan, R., Kuriyan, J., Brenner, S. E., Weiss, A., Puck, J. M.
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<strong>A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70.</strong>
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J. Exp. Med. 213: 155-165, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26783323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26783323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26783323[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=26783323" 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.20150888" target="_blank">Full Text</a>]
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<a id="Colucci2002" class="mim-anchor"></a>
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Colucci, F., Schweighoffer, E., Tomasello, E., Turner, M., Ortaldo, J. R., Vivier, E., Tybulewicz, V. L. J., Di Santo, J. P.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11836527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11836527</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11836527" 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/ni764" target="_blank">Full Text</a>]
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<a id="Crespo2003" class="mim-anchor"></a>
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Crespo, M., Bosch, F., Villamor, N., Bellosillo, B., Colomer, D., Rozman, M., Marce, S., Lopez-Guillermo, A., Campo, E., Montserrat, E.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12724482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12724482</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12724482" 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/10.1056/NEJMoa023143" target="_blank">Full Text</a>]
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<a id="Elder1994" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8202712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8202712</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8202712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.8202712" target="_blank">Full Text</a>]
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Gu, Y., Chae, H.-D., Siefring, J. E., Jasti, A. C., Hildeman, D. A., Williams, D. A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17028588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17028588</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17028588" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF00189976" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15329427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15329427</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15329427" 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/10.1056/NEJMoa040857" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/35020093" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s003359900345" target="_blank">Full Text</a>]
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<a id="Sakaguchi2003" class="mim-anchor"></a>
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Sakaguchi, N., Takahashi, T., Hata, H., Nomura, T., Tagami, T., Yamazaki, S., Sakihama, T., Matsutani, T., Negishi, I., Nakatsuru, S., Sakaguchi, S.
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<strong>Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14647385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14647385</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14647385" 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/nature02119" target="_blank">Full Text</a>]
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Sasahara2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sasahara, Y., Rachid, R., Byrne, M. J., de la Fuente, M. A., Abraham, R. T., Ramesh, N., Geha, R. S.
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<strong>Mechanism of recruitment of WASP to the immunological synapse and of its activation following TCR ligation.</strong>
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Molec. Cell 10: 1269-1281, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12504004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12504004</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12504004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s1097-2765(02)00728-1" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Toyabe2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Toyabe, S.-I., Watanabe, A., Harada, W., Karasawa, T., Uchiyama, M.
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<strong>Specific immunoglobulin E responses in ZAP-70-deficient patients are mediated by Syk-dependent T-cell receptor signalling.</strong>
|
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Immunology 103: 164-171, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11412303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11412303</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11412303[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=11412303" 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/10.1046/j.1365-2567.2001.01246.x" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Watts1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Watts, J. D., Brabb, T., Bures, E. J., Wange, R. L., Samelson, L. E., Aebersold, R.
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<strong>Identification and characterization of a substrate specific for the T cell protein tyrosine kinase ZAP-70.</strong>
|
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FEBS Lett. 398: 217-222, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8977110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8977110</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8977110" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0014-5793(96)01241-0" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 03/14/2019
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 6/27/2016<br>Victor A. McKusick - updated : 9/13/2004<br>Ada Hamosh - updated : 12/1/2003<br>Victor A. McKusick - updated : 6/6/2003<br>Stylianos E. Antonarakis - updated : 4/28/2003<br>Paul J. Converse - updated : 2/11/2002<br>Paul J. Converse - updated : 7/17/2001<br>Ada Hamosh - updated : 8/2/2000<br>Jennifer P. Macke - updated : 5/27/1998<br>Victor A. McKusick - updated : 2/12/1997
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 12/3/1992
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 05/27/2020
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 03/18/2019<br>mgross : 03/14/2019<br>mgross : 03/14/2019<br>carol : 07/07/2016<br>alopez : 6/28/2016<br>ckniffin : 6/27/2016<br>carol : 2/10/2015<br>mcolton : 2/9/2015<br>mgross : 2/11/2014<br>mcolton : 1/23/2014<br>joanna : 12/14/2012<br>carol : 10/25/2012<br>tkritzer : 9/14/2004<br>terry : 9/13/2004<br>joanna : 3/17/2004<br>alopez : 12/2/2003<br>terry : 12/1/2003<br>tkritzer : 6/12/2003<br>tkritzer : 6/12/2003<br>tkritzer : 6/11/2003<br>terry : 6/6/2003<br>mgross : 4/28/2003<br>carol : 4/8/2002<br>alopez : 3/12/2002<br>alopez : 2/11/2002<br>alopez : 2/11/2002<br>alopez : 2/11/2002<br>mgross : 7/17/2001<br>mgross : 7/17/2001<br>alopez : 8/2/2000<br>carol : 8/18/1998<br>carol : 8/3/1998<br>dholmes : 5/27/1998<br>dholmes : 5/27/1998<br>dholmes : 4/16/1998<br>terry : 2/12/1997<br>terry : 2/7/1997<br>mimadm : 2/25/1995<br>carol : 1/27/1995<br>jason : 6/21/1994<br>carol : 12/3/1992
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</span>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 176947
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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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ZETA-CHAIN-ASSOCIATED PROTEIN KINASE; ZAP70
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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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SYK-RELATED TYROSINE KINASE; SRK<br />
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PROTEIN TYROSINE KINASE ZAP70<br />
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ZETA-ASSOCIATED PROTEIN, 70-KD
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ZAP70</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 2q11.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:97,713,576-97,756,364 </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="2">
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<span class="mim-font">
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2q11.2
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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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Autoimmune disease, multisystem, infantile-onset, 2
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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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617006
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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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<tr>
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<td>
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<span class="mim-font">
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Immunodeficiency 48
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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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269840
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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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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The ZAP70 gene encodes a tyrosine kinase that is a critical T-cell signaling molecule that interacts with the zeta-chain (CD247; 186780) of the T-cell receptor (TCR). It is expressed predominantly in T and NK cells (summary by Chan et al., 2016). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Chan et al. (1992) isolated a cDNA encoding a 70-kD tyrosine phosphoprotein, ZAP70, that associates with the zeta chain and undergoes tyrosine phosphorylation following TCR stimulation. The ZAP70 gene is expressed in T- and natural killer 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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<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>Chan et al. (1994) mapped the ZAP70 gene to chromosome 2q12 by hybridization of a genomic fragment to human/rodent somatic hybrid cell DNA and by fluorescence in situ hybridization (FISH). Ku et al. (1994) likewise assigned the ZAP70 gene to 2q12 by isotopic in situ hybridization. They mapped the murine homolog to mouse chromosome 1 by the same method. Saito et al. (1997) also mapped the gene to mouse chromosome 1 and rat chromosome 9q22.1 by FISH; by genetic linkage analysis, they further refined the location of the gene on mouse chromosome 1. </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>Watts et al. (1996) identified a ZAP70 phosphorylation site on the erythrocyte band-3 protein (see 109270) cytoplasmic fragment. They found that this phosphorylation site is distinct from the phosphorylation sites for other PTKs. </p><p>Animals deficient in pre-TCR-alpha have few alpha-beta lineage cells but an increased number of gamma-delta T cells. These gamma-delta T cells exhibit more extensive TCR-beta rearrangement than gamma-delta T cells from wildtype mice. These observations are consistent with the idea that different signals emanating from the gamma-delta-TCR and pre-TCR instruct lineage commitment. Using confocal microscopy and biochemistry to analyze the initiation of signaling, Saint-Ruf et al. (2000) showed that the pre-TCR, but not the gamma-delta TCR, colocalizes with the p56(lck) Src kinase (153390) into glycolipid-enriched membrane domains (rafts) apparently without any need for ligation. This results in the phosphorylation of CD3-epsilon (186830) and ZAP70 signal transducing molecules. Saint-Ruf et al. (2000) stated that their results indicated clear differences between pre-TCR and gamma-delta-TCR signaling. </p><p>Colucci et al. (2002) noted that humans with mutations in ZAP70 have T-cell immunodeficiency, that mice lacking Zap70 have blocked T-cell development, and that mice lacking Syk (600085) have a failure of B-cell development. NK cells express both molecules, which associate with immunoreceptor tyrosine-based activation motifs (ITAMs). Using mice deficient in both Zap70 and Syk, Colucci et al. (2002) observed NK cell activity comparable to that in wildtype mice. The mutant cells expressed Nkg2d (602893) and were able to lyse targets with and without Nkg2d ligands in vitro and in vivo. However, wildtype cells, but not the double-deficient cells, responded to CD16 (146740) and Ly49d (see 604274) cross-linking with increased cytotoxicity, suggesting that these 2 ITAM-bearing receptors are unable to signal in the mutant cells. Inhibitors of PI3K (see 601232) or Src kinases blocked and, in combination, abrogated cytotoxic activity in the mutant cells, whereas inhibition of both kinases was required to reduce wildtype NK activity. Colucci et al. (2002) concluded that intracellular signaling in the adaptive immune system, i.e., in B and T cells, is fundamentally different from that in the NK cells of the innate immune system. </p><p>Sasahara et al. (2002) showed that the adaptor protein CRKL (602007) binds directly to WIP (602357) and that, following T-cell receptor ligation, a CRKL-WIP-WASP (300392) complex is recruited by ZAP70 to lipid rafts and immunologic synapses. </p><p>Crespo et al. (2003) found that ZAP70 expression by cells in chronic lymphocytic leukemia (CLL; 151400), as ascertained by flow cytometric analysis, is a simple and reliable surrogate for the identification of immunoglobulin heavy chain variable region gene (IGHV; see 147070) mutations. Moreover, ZAP70 expression by itself can be used as a prognostic marker. For these reasons, they urged that ZAP70 analysis be included in the workup of patients with CLL. </p><p>Using in vitro binding assays, Gu et al. (2006) showed that Rhoh (602037) interacted with Zap70. The Rhoh-Zap70 interaction depended mainly on conserved tyrosine-phosphorylated ITAMs in Rhoh and the SH2 domains in Zap70. Rhoh was required for proper recruitment of Zap70 to plasma membrane and cytoskeleton fractions in thymocytes and consequently for activation of Zap70 in TCR signal transduction. Based on these findings and studies in Rhoh -/- mice, Gu et al. (2006) concluded that RHOH is a critical regulator of thymocyte development and TCR signaling via its recruitment and activation of ZAP70. </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>
|
|
<span class="mim-font">
|
|
<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">
|
|
<p><strong><em>Immunodeficiency 48</em></strong></p><p>
|
|
In 3 affected females from 2 Mennonite families with immunodeficiency-48 (IMD48; 269840) characterized by a selective T-cell defect, Arpaia et al. (1994) identified a homozygous mutation in the ZAP70 (176947.0001), resulting in loss of the activity of this kinase. The mutation was present in heterozygous state in the parents and 3 unaffected sibs. </p><p>In 3 sibs, 2 boys and a girl, with IMD48, Chan et al. (1994) identified compound heterozygous mutations in the ZAP70 gene (176947.0002 and 176947.0003). </p><p>In a female infant with IMD48, Elder et al. (1994) identified a homozygous mutation in the ZAP70 gene (176947.0004). The parents and unaffected sibs were heterozygous for the mutation. </p><p><strong><em>Chronic Lymphocytic Leukemia</em></strong></p><p>
|
|
Rassenti et al. (2004) noted that in cases of aggressive chronic lymphocytic leukemia (151400), CLL cells usually express an unmutated immunoglobulin heavy chain variable region gene (IGHV; see 147070) and ZAP70 gene, whereas in cases of indolent disease, CLL cells usually express a mutated immunoglobulin heavy chain variable region gene but lack expression of ZAP70. In studies of 307 patients with CLL, Rassenti et al. (2004) found that although the presence of an unmutated immunoglobulin heavy chain variable region gene was strongly associated with expression of ZAP70, ZAP70 was a stronger predictor of the need for treatment in B-cell CLL. </p><p><strong><em>Infantile-Onset Multisystem Autoimmune Disease 2</em></strong></p><p>
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In 2 sibs with infantile-onset multisystem autoimmune disease-2 (ADMIO2; 617006), Chan et al. (2016) identified compound heterozygous missense mutations in the ZAP70 gene (R192W, 176947.0006 and R360P, 176947.0007). The mutations were found by whole-exome sequencing and segregated with the disorder in the family. Studies of transfected cell lines and cells from the carrier parents showed that the R192W was a hypomorphic allele with reduced binding to phosphorylated zeta-chain (CD247; 186780) of the TCR, whereas R360P was weakly hyperactive compared to wildtype, most likely due to disruption of the autoinhibitory mechanism. The combination of hypomorphic and activating mutations suggested a novel disease mechanism resulting in a theretofore undescribed human ZAP70-associated autoimmune disease. </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>Sakaguchi et al. (2003) reported that the SKG strain, which is derived from a closed breeding colony of BALB/c mice, spontaneously develops chronic arthritis. Joint swelling with hyperemia became macroscopically evident in SKG mice at about 2 months of age, initially at a few interphalangeal joints of the forepaws, then progressing in a symmetrical fashion to swelling of the other finger joints of the forepaws and hindpaws and larger joints (wrists and ankles). Knee, elbow, shoulder, or vertebral joints were rarely affected except for the joint at the base of the tail in aged SKG mice. Radiographic examination revealed destruction and fusion of the subchondral bones, joint dislocation, and osteoporosis by 8 to 12 months of age. Despite suffering from such severe chronic arthritis, most SKG mice survived well to 1 year of age, generally with more severe arthritides in females. Sakaguchi et al. (2003) found that this arthritis is an autosomal recessive trait. They found a tryptophan-to-cysteine substitution at residue 163 (W163C) at the start of the second SH2 domain of ZAP70. Altered signal transduction from T-cell antigen receptor (see 186740) through the aberrant ZAP70 changes the threshold of T cells to thymic selection, leading to the positive selection of otherwise negatively selected autoimmune T cells. Sakaguchi et al. (2003) speculated that thymic production of arthritogenic T cells due to a genetically determined selection shift of the T-cell repertoire towards high self-reactivity might be crucial to the development of disease in a subset of patients with rheumatoid arthritis. </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>7 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 IMMUNODEFICIENCY 48</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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ZAP70, IVS, G-A, -11
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<br />
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SNP: rs730880318,
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gnomAD: rs730880318,
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ClinVar: RCV000014158, RCV000726208, RCV001851845, RCV003390681
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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 3 females in 2 different families from a genetically isolated Mennonite community in Ontario, Arpaia et al. (1994) demonstrated that immunodeficiency-48 (IMD48; 269840) due to a selective T-cell defect was the result of homozygosity for a splice mutation in the ZAP70 gene. An intronic point mutation created a new splice acceptor site with the insertion of 9 nucleotides in the mRNA and 3 additional amino acids in the protein product. The G-to-A transition at position -11 from the 3-prime end of the intron created an AluI restriction site which Arpaia et al. (1994) used for identifying heterozygotes in the family. Both parents were carriers and 3 of 4 sibs were heterozygous as well. The mutation resulted in an unstable protein that could not be detected by Western blotting or kinase activity. </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 IMMUNODEFICIENCY 48</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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ZAP70, IVS, G-A, -9
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<br />
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ClinVar: RCV000014158, RCV000726208, RCV001851845, RCV003390681
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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 brothers and a sister with immunodeficiency-48 (IMD48; 269840), Chan et al. (1994) identified compound heterozygous mutations in the ZAP70 gene. One mutation, inherited from the mother, was a 9-bp insertion due to a G-to-A transition within an intron 9-bp upstream of the normal splice acceptor site. The mutation resulted in a more favored splice acceptor site (AGC rather than AGA) and in the addition of 3 amino acids, leu-glu-gln, within the catalytic domain of the ZAP70 protein. The other mutation, inherited from the father, was a 1763C-A transition resulting in a ser518-to-arg (S518R; 176947.0003) substitution. Ser518 is in a highly conserved region of the catalytic domain of the ZAP70 protein. </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 IMMUNODEFICIENCY 48</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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ZAP70, SER518ARG
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<br />
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SNP: rs104893674,
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ClinVar: RCV000033208
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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>For discussion of the ser518-to-arg (S518R) mutation in the ZAP70 gene that was found in compound heterozygous state in patients with immunodeficiency-48 (IMD48; 269840) by Chan et al. (1994), see 176947.0002. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0004 IMMUNODEFICIENCY 48</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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ZAP70, 13-BP DEL, NT1719
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<br />
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SNP: rs730880319,
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ClinVar: RCV000014164, RCV005089250
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 1-year-old female with immunodeficiency-48 (IMD48; 269840), Elder et al. (1994) demonstrated homozygosity for a 13-bp deletion involving nucleotides 1719-1731 (1719_1931del13) of the ZAP70 gene. The deletion would be expected to cause a translational frameshift after amino acid 503, resulting in premature termination 35 codons downstream and yielding a mutant protein 82 residues shorter than the wildtype. Both parents and 2 unaffected sibs were heterozygous for the mutation. </p>
|
|
</span>
|
|
</div>
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|
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<div>
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|
<br />
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|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 IMMUNODEFICIENCY 48</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
ZAP70, ARG465HIS
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|
<br />
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|
|
SNP: rs137853201,
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|
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|
|
|
gnomAD: rs137853201,
|
|
|
|
|
|
ClinVar: RCV000033214, RCV001305022
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 8-month-old girl with immunodeficiency-48 (IMD48; 269840), Toyabe et al. (2001) detected a homozygous 1603G-A transition in the ZAP70 gene, resulting in an arg465-to-his substitution in the kinase domain. The patient lacked CD8-positive T cells but had normal CD4-positive T cells and serum Ig levels. ZAP70-deficient patients rarely have antigen-specific antibodies, but this patient developed specific IgE antibodies (see 147050) to food allergens without developing food allergies. Stimulation of peripheral blood mononuclear cells with phorbol myristate acetate, but not with other mitogens, resulted in production of high levels of IL4 (147780), T-cell expression of CD40L (300386), and expression of germline and mature IgE epsilon transcripts in B cells. Western blot analysis showed expression of high levels of SYK (600085) in T cells from the patient, which also expressed high levels of CD40L, but not in those from controls. A protein tyrosine kinase/SYK inhibitor aborted IL4 production and CD40L expression. Toyabe et al. (2001) proposed that partial T-cell function and a T-cell receptor-signaling pathway can be retained in some ZAP70-deficient patients via SYK. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 2 (1 family)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ZAP70, ARG192TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199840952,
|
|
|
|
|
|
gnomAD: rs199840952,
|
|
|
|
|
|
ClinVar: RCV000208562, RCV000227350, RCV001559120, RCV001853323
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs with infantile-onset multisystem autoimmune disease-2 (ADMIO2; 617006), Chan et al. (2016) identified compound heterozygous mutations in the ZAP70 gene: a c.574C-T transition (c.574C-T, NM_001079.3) in exon 5, resulting in an arg192-to-trp (R192W) substitution in the phosphotyrosine-binding pocket, and a c.1079G-C transversion in exon 9, resulting in an arg360-to-pro (R360P; 176947.0007) substitution in the N-lobe of the kinase domain. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Transfection of the mutations into HEK293 T cells showed that the R192W mutant had reduced association with phosphorylated zeta-chains, consistent with it being a hypomorphic allele. Transfection of the R360P mutant did not result in constitutive LAT phosphorylation, but nearby D327P and K362E mutants did cause increased activity, suggesting that all these mutations may interfere with proper autoinhibition of ZAP70. Further studies in another T-cell line indicated that the R360P mutant is weakly hyperactive due to disruption of its autoinhibitory mechanism. Patient cells were not available because both patients had undergone hematopoietic stem cell transplantation, but studies of cells from the heterozygous parents were consistent with R192W being a hypoactive mutant and R360P being weakly hyperactive. Finally, double-transfected cells showed that the R360P phenotype was masked by wildtype ZAP70 and revealed only in the presence of the hypoactive R192W allele. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 2 (1 family)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ZAP70, ARG360PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs869025224,
|
|
|
|
|
|
|
|
ClinVar: RCV000208547, RCV000233631, RCV001559121
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.1079G-C transversion (c.1079G-C, NM_001079.3) in exon 9 of the ZAP70 gene, resulting in an arg360-to-pro (R360P) substitution, that was found in compound heterozygous state in 2 sibs with infantile-onset multisystem autoimmune disease-2 (ADMIO2; 617006) by Chan et al. (2016), see 176947.0006. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Arpaia, E., Shahar, M., Dadi, H., Cohen, A., Roifman, C. M.
|
|
<strong>Defective T cell receptor signaling and CD8(+) thymic selection in humans lacking Zap-70 kinase.</strong>
|
|
Cell 76: 947-958, 1994.
|
|
|
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|
|
[PubMed: 8124727]
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|
[Full Text: https://doi.org/10.1016/0092-8674(94)90368-9]
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</p>
|
|
</li>
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Chan, A. C., Iwashima, M., Turck, C. W., Weiss, A.
|
|
<strong>ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain.</strong>
|
|
Cell 71: 649-662, 1992.
|
|
|
|
|
|
[PubMed: 1423621]
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|
|
[Full Text: https://doi.org/10.1016/0092-8674(92)90598-7]
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</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Chan, A. C., Kadlecek, T. A., Elder, M. E., Filipovich, A. H., Kuo, W.-L., Iwashima, M., Parslow, T. G., Weiss, A.
|
|
<strong>ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency.</strong>
|
|
Science 264: 1599-1601, 1994.
|
|
|
|
|
|
[PubMed: 8202713]
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|
|
[Full Text: https://doi.org/10.1126/science.8202713]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Chan, A. Y., Punwani, D., Kadlecek, T. A., Cowan, M. J., Olson, J. L., Mathes, E. F., Sunderam, U., Fu, S. M., Srinivasan, R., Kuriyan, J., Brenner, S. E., Weiss, A., Puck, J. M.
|
|
<strong>A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70.</strong>
|
|
J. Exp. Med. 213: 155-165, 2016.
|
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|
|
[PubMed: 26783323]
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[Full Text: https://doi.org/10.1084/jem.20150888]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Colucci, F., Schweighoffer, E., Tomasello, E., Turner, M., Ortaldo, J. R., Vivier, E., Tybulewicz, V. L. J., Di Santo, J. P.
|
|
<strong>Natural cytotoxicity uncoupled from the Syk and ZAP-70 intracellular kinases.</strong>
|
|
Nature Immun. 3: 288-294, 2002.
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|
[PubMed: 11836527]
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[Full Text: https://doi.org/10.1038/ni764]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Crespo, M., Bosch, F., Villamor, N., Bellosillo, B., Colomer, D., Rozman, M., Marce, S., Lopez-Guillermo, A., Campo, E., Montserrat, E.
|
|
<strong>ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia.</strong>
|
|
New Eng. J. Med. 348: 1764-1775, 2003.
|
|
|
|
|
|
[PubMed: 12724482]
|
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|
|
[Full Text: https://doi.org/10.1056/NEJMoa023143]
|
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Elder, M. E., Lin, D., Clever, J., Chan, A. C., Hope, T. J., Weiss, A., Parslow, T. G.
|
|
<strong>Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase.</strong>
|
|
Science 264: 1596-1599, 1994.
|
|
|
|
|
|
[PubMed: 8202712]
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[Full Text: https://doi.org/10.1126/science.8202712]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Gu, Y., Chae, H.-D., Siefring, J. E., Jasti, A. C., Hildeman, D. A., Williams, D. A.
|
|
<strong>RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development.</strong>
|
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Nature Immun. 7: 1182-1190, 2006.
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