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Entry
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- *300490 - SH2 DOMAIN PROTEIN 1A; SH2D1A
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*300490</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/300490">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li 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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</ul>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000183918;t=ENST00000371139" 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=4068" 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=300490" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000183918;t=ENST00000371139" 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_001114937,NM_002351" 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_002351" 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=300490" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=02390&isoform_id=02390_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/SH2D1A" 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/3153108,3695069,3695071,3928894,3928896,3928898,3928900,3928902,4506923,6094278,18088434,49457015,49457039,119632252,119632253,119632254,119632255,119632256,169234945,189053230,218630131,253776411,307133522,423091977,423091979,423091981" 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/O60880" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=4068" 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=ENSG00000183918;t=ENST00000371139" 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=SH2D1A" 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=SH2D1A" 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+4068" 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/SH2D1A" 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:4068" 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/4068" 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=chrX&hgg_gene=ENST00000371139.9&hgg_start=124346563&hgg_end=124373160&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:10820" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/sh2d1a" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=300490[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=300490[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/ENSG00000183918" 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=SH2D1A" 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=SH2D1A" 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=SH2D1A" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://structure.bmc.lu.se/idbase/SH2D1Abase/" title="SH2D1Abase: Mutation registry for X-linked lymphoproliferative syndrome (XLP)" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">SH2D1Abase: Mutation regis…</a></div><div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/SH2D1A" title="CCHMC - Human Genetics Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">CCHMC - Human Genetics Mut…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SH2D1A&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/PA35728" 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:10820" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1328352" 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/SH2D1A#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:1328352" 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/4068/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=4068" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-060526-212" 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="mimCellLines">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:300490" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</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:4068" 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=SH2D1A&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1162828001<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
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300490
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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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SH2 DOMAIN PROTEIN 1A; SH2D1A
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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>
|
|
<span class="mim-font">
|
|
SIGNALING LYMPHOCYTE ACTIVATION MOLECULE-ASSOCIATED PROTEIN<br />
|
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SLAM-ASSOCIATED PROTEIN; SAP
|
|
</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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SH2D1A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SH2D1A</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/X/655?start=-3&limit=10&highlight=655">Xq25</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:124346563-124373160&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'})">X:124,346,563-124,373,160</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/655?start=-3&limit=10&highlight=655">
|
|
Xq25
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Lymphoproliferative syndrome, X-linked, 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/308240"> 308240 </a>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
|
|
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<p>By positional cloning, <a href="#6" class="mim-tip-reference" title="Coffey, A. J., Brooksbank, R. A., Brandau, O., Oohashi, T., Howell, G. R., Bye, J. M., Cahn, A. P., Durham, J., Heath, P., Wray, P., Pavitt, R., Wilkinson, J., and 31 others. <strong>Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.</strong> Nature Genet. 20: 129-135, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771704</a>] [<a href="https://doi.org/10.1038/2424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771704">Coffey et al. (1998)</a> identified the gene mutated in X-linked lymphoproliferative disease (XLP; <a href="/entry/308240">308240</a>). The SH2 domain protein-1A (SH2D1A) gene encodes a deduced 128-amino acid protein consisting of a 5-amino acid N-terminal sequence, an SH2 domain, and a 25-amino acid C-terminal tail. The absence of a hydrophobic signal sequence suggests that SH2D1A is localized in the cytoplasm. Northern blot analysis detected a 2.5-kb SH2D1A mRNA expressed at high levels in thymus and lung, with a lower level of expression in spleen and liver. SH2D1A expression was also detected by RT-PCR in all lymphocyte populations assayed, but was not detected in a range of EBV-transformed lymphoblastoid cell lines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771704" 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>To determine the signaling mechanism of SLAM (signaling lymphocyte activation molecule; <a href="/entry/603492">603492</a>), a glycosylated transmembrane protein also known as CDw150 or CD150, <a href="#26" class="mim-tip-reference" title="Sayos, J., Wu, C., Morra, M., Wang, N., Zhang, X., Allen, D., van Schaik, S., Notarangelo, L., Gehat, R., Roncarolo, M. G., Oettgen, H., De Vries, J. E., Aversall, G., Terhorst, C. <strong>The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM.</strong> Nature 395: 462-469, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774102</a>] [<a href="https://doi.org/10.1038/26683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774102">Sayos et al. (1998)</a> identified the SH2D1A gene, which they referred to as SAP for 'SLAM-associated protein.' The predicted 128-amino acid human SAP protein is 96% homologous to the murine protein in both the SH2 and tail domains. In both humans and in mice, SAP is expressed in all major subsets of T cells, including CD4+, CD45RO+, CD45RA+, and CD8+, but not in B cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9774102" 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="#6" class="mim-tip-reference" title="Coffey, A. J., Brooksbank, R. A., Brandau, O., Oohashi, T., Howell, G. R., Bye, J. M., Cahn, A. P., Durham, J., Heath, P., Wray, P., Pavitt, R., Wilkinson, J., and 31 others. <strong>Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.</strong> Nature Genet. 20: 129-135, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771704</a>] [<a href="https://doi.org/10.1038/2424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771704">Coffey et al. (1998)</a> determined that the SH2D1A gene contains 4 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771704" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By positional cloning, <a href="#6" class="mim-tip-reference" title="Coffey, A. J., Brooksbank, R. A., Brandau, O., Oohashi, T., Howell, G. R., Bye, J. M., Cahn, A. P., Durham, J., Heath, P., Wray, P., Pavitt, R., Wilkinson, J., and 31 others. <strong>Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.</strong> Nature Genet. 20: 129-135, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771704</a>] [<a href="https://doi.org/10.1038/2424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771704">Coffey et al. (1998)</a> identified the SH2D1A gene within the X-linked lymphoproliferative disease critical region on Xq25. Using a clone that contained all 4 exons of mouse Sap, <a href="#26" class="mim-tip-reference" title="Sayos, J., Wu, C., Morra, M., Wang, N., Zhang, X., Allen, D., van Schaik, S., Notarangelo, L., Gehat, R., Roncarolo, M. G., Oettgen, H., De Vries, J. E., Aversall, G., Terhorst, C. <strong>The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM.</strong> Nature 395: 462-469, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774102</a>] [<a href="https://doi.org/10.1038/26683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774102">Sayos et al. (1998)</a> localized the gene to the part of the mouse X chromosome corresponding to human Xq25. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9774102+9771704" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#11" class="mim-tip-reference" title="Lappalainen, I., Giliani, S., Franceschini, R., Bonnefoy, J.-Y., Duckett, C., Notarangelo, L. D., Vihinen, M. <strong>Structural basis for SH2D1A mutations in X-linked lymphoproliferative disease.</strong> Biochem. Biophys. Res. Commun. 269: 124-130, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10694488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10694488</a>] [<a href="https://doi.org/10.1006/bbrc.2000.2146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10694488">Lappalainen et al. (2000)</a> developed a 3-dimensional model of the SH2 domain of the SH2D1A protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10694488" 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>SLAM is a protein that is centrally involved in the bidirectional stimulation of T and B cells. When activated, it mediates expansion of activated T cells during immune responses, induces production of interferon-gamma, and changes the functional profile of subsets of T cells. Signaling through SLAM-SLAM binding during mutual interaction between B cells, and between B cells and T cells, increases the expansion and differentiation of activated B cells. <a href="#26" class="mim-tip-reference" title="Sayos, J., Wu, C., Morra, M., Wang, N., Zhang, X., Allen, D., van Schaik, S., Notarangelo, L., Gehat, R., Roncarolo, M. G., Oettgen, H., De Vries, J. E., Aversall, G., Terhorst, C. <strong>The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM.</strong> Nature 395: 462-469, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774102</a>] [<a href="https://doi.org/10.1038/26683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774102">Sayos et al. (1998)</a> found that SAP binding blocks the recruitment of the tyrosine phosphatase SHP2 (<a href="/entry/176876">176876</a>) to the phosphorylated cytoplasmic domain of SLAM, suggesting that SAP is a natural inhibitor of SLAM. Upon T-cell activation, SLAM may switch from a signaling cascade that is dependent on SAP, and probably on FYN (<a href="/entry/137025">137025</a>), a member of the src tyrosine kinase family, to one that depends on SHP2. <a href="#26" class="mim-tip-reference" title="Sayos, J., Wu, C., Morra, M., Wang, N., Zhang, X., Allen, D., van Schaik, S., Notarangelo, L., Gehat, R., Roncarolo, M. G., Oettgen, H., De Vries, J. E., Aversall, G., Terhorst, C. <strong>The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM.</strong> Nature 395: 462-469, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774102</a>] [<a href="https://doi.org/10.1038/26683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774102">Sayos et al. (1998)</a> proposed that SAP controls the signal-transduction pathways initiated by interactions between SLAM molecules at the interface between T and B cells. <a href="#26" class="mim-tip-reference" title="Sayos, J., Wu, C., Morra, M., Wang, N., Zhang, X., Allen, D., van Schaik, S., Notarangelo, L., Gehat, R., Roncarolo, M. G., Oettgen, H., De Vries, J. E., Aversall, G., Terhorst, C. <strong>The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM.</strong> Nature 395: 462-469, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774102</a>] [<a href="https://doi.org/10.1038/26683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774102">Sayos et al. (1998)</a> showed that SAP cDNAs isolated from the blood cells of patients with X-linked lymphoproliferative syndrome did not bind SLAM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9774102" 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="#21" class="mim-tip-reference" title="Poy, F., Yaffe, M. B., Sayos, J., Saxena, K., Morra, M., Sumegi, J., Cantley, L. C., Terhorst, C., Eck, M. J. <strong>Crystal structures of the XLP protein SAP reveal a class of SH2 domains with extended, phosphotyrosine-independent sequence recognition.</strong> Molec. Cell 4: 555-561, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10549287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10549287</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80206-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10549287">Poy et al. (1999)</a> described 3-dimensional protein structures showing that SH2D1A binds phosphorylated and nonphosphorylated SLAM peptides in a similar mode, with the tyrosine- or phosphotyrosine-281 residue inserted into the phosphotyrosine-binding pocket. Specific interactions with residues N-terminal to this tyrosine, in addition to more characteristic C-terminal interactions, stabilize the complexes. SH2D1A interacts via its SH2 domain with the protein sequence motif TIpYXX(V/I). A phosphopeptide library screen and analysis of mutations identified in XLP patients confirmed that these extended interactions are required for SH2D1A function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10549287" 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 binding analysis, <a href="#35" class="mim-tip-reference" title="Tangye, S. G., Lazetic, S., Woollatt, E., Sutherland, G. R., Lanier, L. L., Phillips, J. H. <strong>Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP.</strong> J. Immun. 162: 6981-6985, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10358138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10358138</a>]" pmid="10358138">Tangye et al. (1999)</a> found that phosphorylated 2B4 (<a href="/entry/605554">605554</a>), a protein with significant homology to SLAM, recruits either SHP2 or SAP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10358138" 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="#34" class="mim-tip-reference" title="Sylla, B. S., Murphy, K., Cahir-McFarland, E., Lane, W. S., Mosialos, G., Kieff, E. <strong>The X-linked lymphoproliferative syndrome gene product SH2D1A associates with p62(dok) (Dok1) and activates NF-kappa-beta.</strong> Proc. Nat. Acad. Sci. 97: 7470-7475, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10852966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10852966</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10852966[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/10.1073/pnas.130193097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10852966">Sylla et al. (2000)</a> reported that SH2D1A associates with DOK1 (<a href="/entry/602919">602919</a>), a protein that interacts with RAS-GAP, cytoplasmic tyrosine kinase (CSK; <a href="/entry/124095">124095</a>), and NCK (see NCK1; <a href="/entry/600508">600508</a>). They found that an SH2D1A SH domain mutant found in XLP does not associate with Dok1, suggesting this interaction is linked to XLP. Other evidence indicated that SH2D1A can affect multiple intracellular signaling pathways that are potentially important in the normal effective host response to Epstein-Barr virus (EBV) infection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10852966" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Morra, M., Simarro-Grande, M., Martin, M., Chen, A. S.-I., Lanyi, A., Silander, O., Calpe, S., Davis, J., Pawson, T., Eck, M. J., Sumegi, J., Engel, P., Li, S.-C., Terhorst, C. <strong>Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients.</strong> J. Biol. Chem. 276: 36809-36816, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11477068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11477068</a>] [<a href="https://doi.org/10.1074/jbc.M101305200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11477068">Morra et al. (2001)</a> stated that SH2D1A interacts via its SH2 domain with a motif (TIYXXV) present in the cytoplasmic tail of the cell-surface receptors CD150 (SLAM), CD84 (<a href="/entry/604513">604513</a>), CD229 (LY9; <a href="/entry/600684">600684</a>), and CD244 (2B4). <a href="#15" class="mim-tip-reference" title="Morra, M., Simarro-Grande, M., Martin, M., Chen, A. S.-I., Lanyi, A., Silander, O., Calpe, S., Davis, J., Pawson, T., Eck, M. J., Sumegi, J., Engel, P., Li, S.-C., Terhorst, C. <strong>Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients.</strong> J. Biol. Chem. 276: 36809-36816, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11477068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11477068</a>] [<a href="https://doi.org/10.1074/jbc.M101305200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11477068">Morra et al. (2001)</a> analyzed the effect of SH2D1A protein missense mutations identified in 10 XLP families and found that the mutant proteins clustered into 2 major groups: mutants with a markedly decreased half-life, and mutants with structural changes that variably affect their interaction with the 4 receptors. Because there was no correlation between the type of mutation and clinical presentation, <a href="#15" class="mim-tip-reference" title="Morra, M., Simarro-Grande, M., Martin, M., Chen, A. S.-I., Lanyi, A., Silander, O., Calpe, S., Davis, J., Pawson, T., Eck, M. J., Sumegi, J., Engel, P., Li, S.-C., Terhorst, C. <strong>Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients.</strong> J. Biol. Chem. 276: 36809-36816, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11477068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11477068</a>] [<a href="https://doi.org/10.1074/jbc.M101305200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11477068">Morra et al. (2001)</a> concluded that unidentified genetic or environmental factors must play a strong role in XLP disease manifestations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11477068" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Hwang, P. M., Li, C., Morra, M., Lillywhite, J., Muhandiram, D. R., Gertler, F., Terhorst, C., Kay, L. E., Pawson, T., Forman-Kay, J. D., Li, S.-C. <strong>A 'three-pronged' binding mechanism for the SAP/SH2D1A SH2 domain: structural basis and relevance to the XLP syndrome.</strong> EMBO J. 21: 314-323, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11823424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11823424</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11823424[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/10.1093/emboj/21.3.314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11823424">Hwang et al. (2002)</a> screened a repertoire of synthetic peptides and stated that the consensus motif for binding is T/SXXXXV/I. This motif is unusual in that it contains neither a tyrosine nor a phosphotyrosine residue, hallmarks of conventional SH2 domain-ligand interactions. The NMR-determined structures of the protein in complex with 2 distinct peptides provided direct evidence in support of a '3-pronged,' more versatile, binding mechanism for the SH2D1A SH2 domain, in contrast to the '2-pronged' binding for conventional SH2 domains. <a href="#10" class="mim-tip-reference" title="Hwang, P. M., Li, C., Morra, M., Lillywhite, J., Muhandiram, D. R., Gertler, F., Terhorst, C., Kay, L. E., Pawson, T., Forman-Kay, J. D., Li, S.-C. <strong>A 'three-pronged' binding mechanism for the SAP/SH2D1A SH2 domain: structural basis and relevance to the XLP syndrome.</strong> EMBO J. 21: 314-323, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11823424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11823424</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11823424[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/10.1093/emboj/21.3.314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11823424">Hwang et al. (2002)</a> noted that all of the mutants examined in their study showed markedly reduced affinities for the nonphosphorylated SLAM peptide, suggesting that phosphorylation-independent interactions mediated by SH2D1A likely play an important role in the pathogenesis of XLP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11823424" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using an array of peptides derived from the SLAM family of receptors, <a href="#13" class="mim-tip-reference" title="Li, C., Iosef, C., Jia, C. Y. H., Han, V. K. M., Li, S. S.-C. <strong>Dual functional roles for the X-linked lymphoproliferative syndrome gene product SAP/SH2D1A in signaling through the signaling lymphocyte activation molecule (SLAM) family of immune receptors.</strong> J. Biol. Chem. 278: 3852-3859, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12458214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12458214</a>] [<a href="https://doi.org/10.1074/jbc.M206649200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12458214">Li et al. (2003)</a> demonstrated that SH2D1A binds with comparable affinities to the same sites in those receptors as do the SH2 domains of SHP2 and SH2-containing inositol phosphatase (SHIP; <a href="/entry/601582">601582</a>), suggesting that the 3 proteins may compete against one another in binding to a given SLAM family receptor. Furthermore, in vitro and in vivo binding studies indicated that SH2D1A is capable of binding directly to the T cell-specific tyrosine kinase FYN (<a href="/entry/137025">137025</a>), an interaction mediated by the FYN SH3 domain. In cells, FYN was shown to be indispensable for SLAM tyrosine phosphorylation, which, in turn, was dramatically enhanced by SH2D1A. Because SH2D1A also blocked the recruitment of SHP2 to SLAM, <a href="#13" class="mim-tip-reference" title="Li, C., Iosef, C., Jia, C. Y. H., Han, V. K. M., Li, S. S.-C. <strong>Dual functional roles for the X-linked lymphoproliferative syndrome gene product SAP/SH2D1A in signaling through the signaling lymphocyte activation molecule (SLAM) family of immune receptors.</strong> J. Biol. Chem. 278: 3852-3859, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12458214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12458214</a>] [<a href="https://doi.org/10.1074/jbc.M206649200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12458214">Li et al. (2003)</a> proposed a dual functional role for SH2D1A in SLAM signaling, acting as both an adaptor for FYN and an inhibitor to SHP2 binding. They concluded that this dual role is likely to be physiologically relevant, since disease-causing SH2D1A mutants exhibited significantly reduced affinities to both FYN and SLAM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12458214" 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>The cytoplasmic protein encoded by the SH2D1A gene plays an essential role in controlling EBV infection. It is expressed in T and NK cells, but not in B cells or in granulocytes. <a href="#18" class="mim-tip-reference" title="Parolini, O., Weinhausel, A., Kagerbauer, B., Sassmann, J., Holter, W., Gadner, H., Haas, O. A., Knapp, W. <strong>Differential methylation pattern of the X-linked lymphoproliferative (XLP) disease gene SH2D1A correlates with the cell lineage-specific transcription.</strong> Immunogenetics 55: 116-121, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12709835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12709835</a>] [<a href="https://doi.org/10.1007/s00251-003-0557-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12709835">Parolini et al. (2003)</a> tested the hypothesis that DNA methylation contributes to tissue-specific SH2D1A gene expression and analyzed the methylation status of 2,300 bp upstream of the ATG starting codon, the coding region, and part of intron 1. By bisulfite sequencing and methylation-sensitive restriction enzyme digestion, they showed that a differential methylation pattern of CpG-rich regions in the 5-prime region and the adjacent exon 1 of the SH2D1A gene indeed correlates with the tissue-specific gene transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12709835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By studying NK-cell function in patients with XLP and a defect in the SAP gene, <a href="#19" class="mim-tip-reference" title="Parolini, S., Bottino, C., Falco, M., Augugliaro, R., Giliani, S., Franceschini, R., Ochs, H. D., Wolf, H., Bonnefoy, J.-Y., Biassoni, R., Moretta, L., Notarangelo, L. D., Moretta, A. <strong>X-linked lymphoproliferative disease: 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells.</strong> J. Exp. Med. 192: 337-346, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10934222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10934222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10934222[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.192.3.337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10934222">Parolini et al. (2000)</a> found that a number of triggering receptors displayed normal function. However, upon 2B4 interaction with CD48 (<a href="/entry/109530">109530</a>), NK-cell function against EBV-infected cells, which is primarily mediated via NKp46 (LY94; <a href="/entry/604530">604530</a>), was inhibited. Disruption of 2B4-CD48 and/or NK receptor-HLA interaction restored NK cytolytic activity. RT-PCR analysis detected the full-length 2B4 cDNA as well as a 2B4 molecule lacking the Ig C2 domain in both patients and normal individuals. Molecular analysis failed to reveal any differences between normal and patient 2B4 sequences. Immunoblot analysis showed that treatment of normal but not XLP NK cells with pervanadate led to the association of 2B4 with SAP. <a href="#19" class="mim-tip-reference" title="Parolini, S., Bottino, C., Falco, M., Augugliaro, R., Giliani, S., Franceschini, R., Ochs, H. D., Wolf, H., Bonnefoy, J.-Y., Biassoni, R., Moretta, L., Notarangelo, L. D., Moretta, A. <strong>X-linked lymphoproliferative disease: 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells.</strong> J. Exp. Med. 192: 337-346, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10934222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10934222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10934222[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.192.3.337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10934222">Parolini et al. (2000)</a> suggested that anti-2B4 treatment might be of use in XLPD patients awaiting bone marrow transplantation. <a href="#36" class="mim-tip-reference" title="Tangye, S. G., Phillips, J. H., Lanier, L. L., Nichols, K. E. <strong>Cutting edge: functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome.</strong> J. Immun. 165: 2932-2936, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10975798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10975798</a>] [<a href="https://doi.org/10.4049/jimmunol.165.6.2932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10975798">Tangye et al. (2000)</a> found that although XLP patient NK cells can be active, the absence of SAP selectively cripples the 2B4-mediated activation pathway. XLPD patient NK cells were unable to lyse CD48-expressing target cells. The authors pointed out that CD48 was originally identified as an antigen whose expression is at least 10-fold greater on EBV-transformed cells than on EBV-negative cells (<a href="#37" class="mim-tip-reference" title="Thorley-Lawson, D. A., Schooley, R. T., Bhan, A. K., Nadler, L. M. <strong>Epstein-Barr virus superinduces a new human B cell differentiation antigen (B-LAST 1) expressed on transformed lymphoblasts.</strong> Cell 30: 415-425, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6291768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6291768</a>] [<a href="https://doi.org/10.1016/0092-8674(82)90239-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6291768">Thorley-Lawson et al., 1982</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10934222+6291768+10975798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Aoukaty, A., Tan, R. <strong>Role for glycogen synthase kinase-3 in NK cell cytotoxicity and X-linked lymphoproliferative disease.</strong> J. Immun. 174: 4551-4558, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15814676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15814676</a>] [<a href="https://doi.org/10.4049/jimmunol.174.8.4551" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15814676">Aoukaty and Tan (2005)</a> found that NK cells from individuals with XLP due to SAP mutations failed to phosphorylate GSK3A (<a href="/entry/606784">606784</a>) and GSK3B (<a href="/entry/605004">605004</a>) after stimulation of 2B4. Lack of GSK3 phosphorylation inactivated GSK3 and prevented accumulation of the transcriptional coactivator beta-catenin (CTNNB1; <a href="/entry/116806">116806</a>) in the cytoplasm and its subsequent translocation to the nucleus. <a href="#1" class="mim-tip-reference" title="Aoukaty, A., Tan, R. <strong>Role for glycogen synthase kinase-3 in NK cell cytotoxicity and X-linked lymphoproliferative disease.</strong> J. Immun. 174: 4551-4558, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15814676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15814676</a>] [<a href="https://doi.org/10.4049/jimmunol.174.8.4551" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15814676">Aoukaty and Tan (2005)</a> identified VAV1 (<a href="/entry/164875">164875</a>), RAC1 (<a href="/entry/602048">602048</a>), RAF1 (<a href="/entry/164760">164760</a>), MEK2 (MAP2K2; <a href="/entry/601263">601263</a>), ERK1 (MAPK3; <a href="/entry/601795">601795</a>), and ERK3 (MAPK6; <a href="/entry/602904">602904</a>) as proteins potentially involved in mediating the signaling pathway between 2B4 and GSK3/CTNNB and found that some of these elements were aberrant in XLP NK cells. <a href="#1" class="mim-tip-reference" title="Aoukaty, A., Tan, R. <strong>Role for glycogen synthase kinase-3 in NK cell cytotoxicity and X-linked lymphoproliferative disease.</strong> J. Immun. 174: 4551-4558, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15814676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15814676</a>] [<a href="https://doi.org/10.4049/jimmunol.174.8.4551" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15814676">Aoukaty and Tan (2005)</a> concluded that GSK3 and beta-catenin mediate signaling of 2B4 in NK cells and that dysfunction of some of the elements in the transduction pathway between 2B4 and GSK3/beta-catenin may result in diminished IFNG (<a href="/entry/147570">147570</a>) secretion and cytotoxic function of NK cells in XLP patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15814676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Latour, S., Gish, G., Helgason, C. D., Humphries, R. K., Pawson, T., Veillette, A. <strong>Regulation of SLAM-mediated signal transduction by SAP, the X-linked lymphoproliferative gene product.</strong> Nature Immun. 2: 681-690, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11477403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11477403</a>] [<a href="https://doi.org/10.1038/90615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11477403">Latour et al. (2001)</a> reported that antibody-mediated ligation of SLAM on thymocytes triggered a protein tyrosine phosphorylation signal in T cells in a SAP-dependent manner. This signal also involved SHIP; the adaptor molecules DOK2 (<a href="/entry/604997">604997</a>), DOK1, and SHC (<a href="/entry/600560">600560</a>); and RASGAP (see <a href="/entry/139150">139150</a>). SAP was crucial for this pathway because it selectively recruited and activated the T-cell isoform of FYN. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11477403" 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="#25" class="mim-tip-reference" title="Sanzone, S., Zeyda, M., Saemann, M. D., Soncini, M., Holter, W., Fritsch, G., Knapp, W., Candotti, F., Stulnig, T. M., Parolini, O. <strong>SLAM-associated protein deficiency causes imbalanced early signal transduction and blocks downstream activation in T cells from X-linked lymphoproliferative disease patients.</strong> J. Biol. Chem. 278: 29593-29599, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12766168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12766168</a>] [<a href="https://doi.org/10.1074/jbc.M300565200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12766168">Sanzone et al. (2003)</a> showed that T cells from patients with XLP were deficient in expression of the activation marker CD25 (IL2RA; <a href="/entry/147730">147730</a>) and in IL2 (<a href="/entry/147680">147680</a>) production in response to T-cell receptor (TCR) stimulation, but not in response to TCR-independent stimulation by phorbol ester. The activation deficiency was associated with diminished VAV and MAP kinase phosphorylation, and it could be reversed by retroviral-mediated SAP gene transfer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12766168" 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 yeast 2-hybrid, immunoblot, and structural analyses, <a href="#5" class="mim-tip-reference" title="Chan, B., Lanyi, A., Song, H. K., Griesbach, J., Simarro-Grande, M., Poy, F., Howie, D., Sumegi, J., Terhorst, C., Eck, M. J. <strong>SAP couples Fyn to SLAM immune receptors.</strong> Nature Cell Biol. 5: 155-160, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12545174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12545174</a>] [<a href="https://doi.org/10.1038/ncb920" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12545174">Chan et al. (2003)</a> showed that the SH2 domain of SAP bound to the SH3 domain of FYN in a noncanonical manner and directly coupled FYN to SLAM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12545174" 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="#17" class="mim-tip-reference" title="Nichols, K. E., Hom, J., Gong, S.-Y., Ganguly, A., Ma, C. S., Cannons, J. L., Tangye, S. G., Schwartzberg, P. L., Koretzky, G. A., Stein, P. L. <strong>Regulation of NKT cell development by SAP, the protein defective in XLP.</strong> Nature Med. 11: 340-345, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15711562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15711562</a>] [<a href="https://doi.org/10.1038/nm1189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15711562">Nichols et al. (2005)</a> observed that Sh2d1a -/- mice lacked NKT cells in the thymus and peripheral organs. The defect in NKT cell ontogeny was hematopoietic cell-autonomous and could be rescued by reconstitution of Sh2d1a expression within Sh2d1a -/- bone marrow cells. <a href="#17" class="mim-tip-reference" title="Nichols, K. E., Hom, J., Gong, S.-Y., Ganguly, A., Ma, C. S., Cannons, J. L., Tangye, S. G., Schwartzberg, P. L., Koretzky, G. A., Stein, P. L. <strong>Regulation of NKT cell development by SAP, the protein defective in XLP.</strong> Nature Med. 11: 340-345, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15711562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15711562</a>] [<a href="https://doi.org/10.1038/nm1189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15711562">Nichols et al. (2005)</a> also studied 17 individuals with XLP and differing SH2D1A genotypes. All 17 lacked NKT cells, and a female XLP carrier showed completely skewed X chromosome inactivation within NKT cells, but not T or B cells. <a href="#17" class="mim-tip-reference" title="Nichols, K. E., Hom, J., Gong, S.-Y., Ganguly, A., Ma, C. S., Cannons, J. L., Tangye, S. G., Schwartzberg, P. L., Koretzky, G. A., Stein, P. L. <strong>Regulation of NKT cell development by SAP, the protein defective in XLP.</strong> Nature Med. 11: 340-345, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15711562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15711562</a>] [<a href="https://doi.org/10.1038/nm1189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15711562">Nichols et al. (2005)</a> concluded that SH2D1A is a crucial regulator of NKT cell ontogeny, and that the absence of NKT cells may contribute to the XLP phenotype, including abnormal antiviral and antitumor immunity and hypogammaglobulinemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15711562" 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>Independently, <a href="#20" class="mim-tip-reference" title="Pasquier, B., Yin, L., Fondaneche, M.-C., Relouzat, F., Bloch-Queyrat, C., Lambert, N., Fischer, A., de Saint-Basile, G., Latour, S. <strong>Defective NKT cell development in mice and humans lacking the adapter SAP, the X-linked lymphoproliferative syndrome gene product.</strong> J. Exp. Med. 201: 695-701, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15738056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15738056</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15738056[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.20042432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15738056">Pasquier et al. (2005)</a> showed that SAP was required for NKT cell development in mice and humans. They proposed that NKT cells may be important in the immune response to EBV. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15738056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By studying TCR restimulation of preactivated T cells from EBV-naive XLP patients after prolonged exposure to IL2, <a href="#29" class="mim-tip-reference" title="Snow, A. L., Marsh, R. A., Krummey, S. M., Roehrs, P., Young, L. R., Zhang, K., van Hoff, J., Dhar, D., Nichols, K. E., Filipovich, A. H., Su, H. C., Bleesing, J. J., Lenardo, M. J. <strong>Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency.</strong> J. Clin. Invest. 119: 2976-2989, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19759517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19759517</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19759517[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI39518" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19759517">Snow et al. (2009)</a> found that activated T cells from these patients were specifically and substantially less sensitive to restimulation-induced cell death (RICD). Silencing SAP or NTBA (SLAMF6; <a href="/entry/606446">606446</a>) expression recapitulated resistance to RICD in normal T cells, indicating that both molecules are necessary for optimal TCR-induced apoptosis. TCR restimulation triggered increased recruitment of SAP to NTBA, and these proteins functioned to augment TCR-induced signal strength and induction of downstream proapoptotic target genes, including FASL (TNFSF6; <a href="/entry/134638">134638</a>) and BIM (BCL2L11; <a href="/entry/603827">603827</a>). <a href="#29" class="mim-tip-reference" title="Snow, A. L., Marsh, R. A., Krummey, S. M., Roehrs, P., Young, L. R., Zhang, K., van Hoff, J., Dhar, D., Nichols, K. E., Filipovich, A. H., Su, H. C., Bleesing, J. J., Lenardo, M. J. <strong>Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency.</strong> J. Clin. Invest. 119: 2976-2989, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19759517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19759517</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19759517[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI39518" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19759517">Snow et al. (2009)</a> proposed that XLP patients are inherently susceptible to antigen-induced lymphoproliferative disease and fulminant infectious mononucleosis due to compromised RICD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19759517" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Nagy, N., Matskova, L., Kis, L. L., Hellman, U., Klein, G., Klein, E. <strong>The proapoptotic function of SAP provides a clue to the clinical picture of X-linked lymphoproliferative disease.</strong> Proc. Nat. Acad. Sci. 106: 11966-11971, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19570996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19570996</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19570996[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/10.1073/pnas.0905691106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19570996">Nagy et al. (2009)</a> found that p53 (TP53; <a href="/entry/191170">191170</a>) was upregulated in activated T cells, and they had previously shown that p53 induces SAP expression in lymphoid cells. Expression of SAP in the Saos-2 human osteosarcoma cell line, which lacks p53, was required to control cell proliferation after irradiation-induced DNA damage. High SAP expression rendered T-ALL tumor cell lines more sensitive to activation-induced cell death, and lymphoblastic cell lines developed from healthy donors, but not those from XLP patients, arrested in G2/M phase of the cell cycle following irradiation. <a href="#16" class="mim-tip-reference" title="Nagy, N., Matskova, L., Kis, L. L., Hellman, U., Klein, G., Klein, E. <strong>The proapoptotic function of SAP provides a clue to the clinical picture of X-linked lymphoproliferative disease.</strong> Proc. Nat. Acad. Sci. 106: 11966-11971, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19570996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19570996</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19570996[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/10.1073/pnas.0905691106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19570996">Nagy et al. (2009)</a> concluded that SAP may be involved in the termination of T-cell responses via activation-induced cell death. They proposed that the absence of functional SAP in XLP patients may allow extended survival of overactivated T cells in infectious mononucleosis, leading to the massive tissue infiltrates and organ failures seen in fatal infectious mononucleosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19570996" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 9 unrelated patients with X-linked lymphoproliferative syndrome, <a href="#6" class="mim-tip-reference" title="Coffey, A. J., Brooksbank, R. A., Brandau, O., Oohashi, T., Howell, G. R., Bye, J. M., Cahn, A. P., Durham, J., Heath, P., Wray, P., Pavitt, R., Wilkinson, J., and 31 others. <strong>Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.</strong> Nature Genet. 20: 129-135, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771704</a>] [<a href="https://doi.org/10.1038/2424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771704">Coffey et al. (1998)</a> identified mutations in the SH2D1A gene (<a href="#0001">300490.0001</a>-<a href="#0009">300490.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771704" 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="#32" class="mim-tip-reference" title="Sumegi, J., Gross, T. G., Seemayer, T. A. <strong>The molecular genetics of X-linked lymphoproliferative (Duncan's) disease.</strong> Cancer J. Sci. Am. 5: 57-62, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10198724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10198724</a>]" pmid="10198724">Sumegi et al. (1999)</a> reviewed the molecular basis of Duncan disease and tabulated 15 mutations in the SH2D1A gene. In 2 brothers with early-onset non-Hodgkin lymphoma, but no clinical or laboratory evidence of EBV infection, <a href="#4" class="mim-tip-reference" title="Brandau, O., Schuster, V., Weiss, M., Hellebrand, H., Fink, F. M., Kreczy, A., Friedrich, W., Strahm, B., Niemeyer, C., Belohradsky, B. H., Meindl, A. <strong>Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP).</strong> Hum. Molec. Genet. 8: 2407-2413, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10556288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10556288</a>] [<a href="https://doi.org/10.1093/hmg/8.13.2407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10556288">Brandau et al. (1999)</a> identified a deletion of exon 1 of the SH2D1A gene (<a href="#0010">300490.0010</a>). Other SH2D1A mutations were identified in 2 additional unrelated patients without evidence of EBV infection; 1 had non-Hodgkin lymphoma and 1 had signs of dysgammaglobulinemia. Development of dysgammaglobulinemia and lymphoma without evidence of prior EBV infection in 4 patients suggested that EBV is unrelated to these particular phenotypes, in contrast to fulminant or fatal infectious mononucleosis. No SH2D1A mutations were found in 3 families in which clinical features were suggestive of XLP. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10198724+10556288" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By PCR, RT-PCR, and sequence analysis of genetic material from 19 typical and 8 atypical XLP patients, <a href="#40" class="mim-tip-reference" title="Yin, L., Ferrand, V., Lavoue, M.-F., Hayoz, D., Philippe, N., Souillet, G., Seri, M., Giacchino, R., Castagnola, E., Hodgson, S., Sylla, B. S., Romeo, G. <strong>SH2D1A mutation analysis for diagnosis of XLP in typical and atypical patients.</strong> Hum. Genet. 105: 501-505, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10598819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10598819</a>] [<a href="https://doi.org/10.1007/s004390051137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10598819">Yin et al. (1999)</a> identified 13 mutations in the SH2D1A gene. One atypical patient reported by <a href="#40" class="mim-tip-reference" title="Yin, L., Ferrand, V., Lavoue, M.-F., Hayoz, D., Philippe, N., Souillet, G., Seri, M., Giacchino, R., Castagnola, E., Hodgson, S., Sylla, B. S., Romeo, G. <strong>SH2D1A mutation analysis for diagnosis of XLP in typical and atypical patients.</strong> Hum. Genet. 105: 501-505, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10598819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10598819</a>] [<a href="https://doi.org/10.1007/s004390051137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10598819">Yin et al. (1999)</a> had initially been diagnosed as having B-cell leukemia, and the diagnosis of XLP was ascertained only after detection of an SH2D1A mutation in the patient's genomic DNA. <a href="#4" class="mim-tip-reference" title="Brandau, O., Schuster, V., Weiss, M., Hellebrand, H., Fink, F. M., Kreczy, A., Friedrich, W., Strahm, B., Niemeyer, C., Belohradsky, B. H., Meindl, A. <strong>Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP).</strong> Hum. Molec. Genet. 8: 2407-2413, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10556288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10556288</a>] [<a href="https://doi.org/10.1093/hmg/8.13.2407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10556288">Brandau et al. (1999)</a> had identified mutations in the SH2D1A gene in 2 independent B-cell leukemia patients. However, <a href="#40" class="mim-tip-reference" title="Yin, L., Ferrand, V., Lavoue, M.-F., Hayoz, D., Philippe, N., Souillet, G., Seri, M., Giacchino, R., Castagnola, E., Hodgson, S., Sylla, B. S., Romeo, G. <strong>SH2D1A mutation analysis for diagnosis of XLP in typical and atypical patients.</strong> Hum. Genet. 105: 501-505, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10598819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10598819</a>] [<a href="https://doi.org/10.1007/s004390051137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10598819">Yin et al. (1999)</a> concluded that the experience in their atypical XLP patient and the negative result of mutation screening in 62 Burkitt lymphoma cell lines (<a href="#41" class="mim-tip-reference" title="Yin, L., Tocco, T., Pauly, S., Lenoir, G. M., Romeo, G. <strong>Absence of SH2D1A point mutation in 62 Burkitts lymphoma cell lines.</strong> Am. J. Hum. Genet. 65 (suppl. 1868): A331 only, 1999."None>Yin et al., 1999</a>) seemed to exclude SH2D1A mutations as causative in B-cell leukemia. <a href="#30" class="mim-tip-reference" title="Strahm, B., Rittweiler, K., Duffner, U., Brandau, O., Orlowska-Volk, M., Karajannis, M. A., zur Stadt, U., Tiemann, M., Reiter, A., Brandis, M., Meindl, A., Niemeyer, C. M. <strong>Recurrent B-cell non-Hodgkin's lymphoma in two brothers with X-linked lymphoproliferative disease without evidence for Epstein-Barr virus infection.</strong> Brit. J. Haemat. 108: 377-382, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10691868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10691868</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2000.01884.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10691868">Strahm et al. (2000)</a> described 2 brothers, previously reported by <a href="#4" class="mim-tip-reference" title="Brandau, O., Schuster, V., Weiss, M., Hellebrand, H., Fink, F. M., Kreczy, A., Friedrich, W., Strahm, B., Niemeyer, C., Belohradsky, B. H., Meindl, A. <strong>Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP).</strong> Hum. Molec. Genet. 8: 2407-2413, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10556288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10556288</a>] [<a href="https://doi.org/10.1093/hmg/8.13.2407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10556288">Brandau et al. (1999)</a>, suffering from recurrent manifestations of B-cell non-Hodgkin lymphoma and recurrent infections of the lower respiratory tract associated with bronchiectasis. Molecular analysis of the SH2D1A gene led to the identification of a deletion in the first exon (<a href="#0010">300490.0010</a>) in both patients. <a href="#30" class="mim-tip-reference" title="Strahm, B., Rittweiler, K., Duffner, U., Brandau, O., Orlowska-Volk, M., Karajannis, M. A., zur Stadt, U., Tiemann, M., Reiter, A., Brandis, M., Meindl, A., Niemeyer, C. M. <strong>Recurrent B-cell non-Hodgkin's lymphoma in two brothers with X-linked lymphoproliferative disease without evidence for Epstein-Barr virus infection.</strong> Brit. J. Haemat. 108: 377-382, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10691868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10691868</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2000.01884.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10691868">Strahm et al. (2000)</a> postulated that the genetic defect identified in the 2 EBV-seronegative brothers with non-Hodgkin lymphoma (<a href="#0010">300490.0010</a>) resulted in a dysregulation of the B-/T-cell interaction, rendering these patients susceptible to the early onset of B-cell non-Hodgkin lymphoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10556288+10598819+10691868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using an SSCP assay for mutation analysis, <a href="#11" class="mim-tip-reference" title="Lappalainen, I., Giliani, S., Franceschini, R., Bonnefoy, J.-Y., Duckett, C., Notarangelo, L. D., Vihinen, M. <strong>Structural basis for SH2D1A mutations in X-linked lymphoproliferative disease.</strong> Biochem. Biophys. Res. Commun. 269: 124-130, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10694488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10694488</a>] [<a href="https://doi.org/10.1006/bbrc.2000.2146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10694488">Lappalainen et al. (2000)</a> identified mutations in the SH2D1A gene in 4 patients with a clinical history of XLP. Noting that a large proportion of SH2D1A mutations lead to truncation of the produced protein, the authors used molecular modeling to show that truncated SH2D1A proteins do not fold and function correctly even if produced. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10694488" 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="#33" class="mim-tip-reference" title="Sumegi, J., Huang, D., Lanyi, A., Davis, J. D., Seemayer, T. A., Maeda, A., Klein, G., Seri, M., Wakiguchi, H., Purtilo, D. T., Gross, T. G. <strong>Correlation of mutations of the SH2D1A gene and Epstein-Barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease.</strong> Blood 96: 3118-3125, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11049992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11049992</a>]" pmid="11049992">Sumegi et al. (2000)</a> reported that analysis of 35 families from the XLP Registry revealed 28 different mutations in 34 families: 3 large genomic deletions, 10 small intragenic deletions, 3 splice site, 3 nonsense, and 9 missense mutations. No mutations were found in 25 males, so-called sporadic XLP (males with an XLP phenotype after EBV infection but no family history of XLP), or in 9 patients with chronic active EBV syndrome. The authors found that although EBV infection often resulted in fulminant infectious mononucleosis, it was not necessary for the expression of other manifestations of XLP and correlated poorly with outcome. They interpreted the results as suggesting that unidentified factors, either environmental or genetic (e.g., modifier genes), contribute to the pathogenesis of XLP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11049992" 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>The phenotype of hemophagocytic lymphohistiocytosis (HPLH; <a href="/entry/267700">267700</a>) bears a strong resemblance to X-linked lymphoproliferative disease. For that reason, <a href="#2" class="mim-tip-reference" title="Arico, M., Imashuku, S., Clementi, R., Hibi, S., Teramura, T., Danesino, C., Haber, D. A., Nichols, K. E. <strong>Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene.</strong> Blood 97: 1131-1133, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159547</a>] [<a href="https://doi.org/10.1182/blood.v97.4.1131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11159547">Arico et al. (2001)</a> analyzed 25 patients diagnosed with HPLH for germline mutations in the SH2D1A gene. They identified 4 patients who had XLP and a mutation in the SH2D1A gene. Two had hemizygous deletions encompassing SH2D1A exon 1 (<a href="#0010">300490.0010</a>) and 2 had nonsense mutations. Among these 4 patients, only 2 had family histories consistent with XLP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11159547" 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="#31" class="mim-tip-reference" title="Sumazaki, R., Kanegane, H., Osaki, M., Fukushima, T., Tsuchida, M., Matsukura, H., Shinozaki, K., Kimura, H., Matsui, A., Miyawaki, T. <strong>SH2D1A mutations in Japanese males with severe Epstein-Barr virus-associated illnesses.</strong> Blood 98: 1268-1270, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11493483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11493483</a>] [<a href="https://doi.org/10.1182/blood.v98.4.1268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11493483">Sumazaki et al. (2001)</a> searched for mutations in the SH2D1A gene in 40 males in Japan who presented with severe EBV-associated illnesses, including fulminant infectious mononucleosis, EBV-positive lymphoma, and severe chronic active EBV infection. SH2D1A mutations were detected in 10 of the patients; 5 of these 10 were sporadic cases. Patients with SH2D1A mutations displayed severe acute infectious mononucleosis with hyperimmunoglobulin M, hypogammaglobulinemia, and B-cell malignant lymphoma. In contrast, chronic active EBV infection was not associated with SH2D1A mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11493483" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Ross, M. T., Grafham, D. V., Coffey, A. J., Scherer, S., McLay, K., Muzny, D., Platzer, M., Howell, G. R., Burrows, C., Bird, C. P., Frankish, A., Lovell, F. L., and 270 others. <strong>The DNA sequence of the human X chromosome.</strong> Nature 434: 325-337, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15772651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15772651</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15772651[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature03440" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15772651">Ross et al. (2005)</a> pointed out that discovery of the relationship between X-linked lymphoproliferative disease and the SH2D1A gene is an example of how the identification of genes involved in rare conditions can yield important biologic insights. In this instance, discovery of mutations in the SH2D1A gene led to identification of a new mediator of signal transduction between T and NK cells, and a novel family of proteins involved in the regulation of the immune response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15772651" 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="#39" class="mim-tip-reference" title="Wu, C., Nguyen, K. B., Pien, G. C., Wang, N., Gullo, C., Duncan, H., Sosa, M. R., Edwards, M. J., Borrow, P., Satoskar, A. R., Sharpe, A. H., Biron, C. A., Terhorst, C. <strong>SAP controls T cell responses to virus and terminal differentiation of T(H)2 cells.</strong> Nature Immun. 2: 410-414, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11323694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11323694</a>] [<a href="https://doi.org/10.1038/87713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11323694">Wu et al. (2001)</a> generated Sap-deficient mice, which were fertile and had no defects in lymphocyte surface markers or overall morphology. Sap-deficient mice had increased lymphocytic choriomeningitis virus (LCMV)-specific splenic and hepatic T cells and increased gamma-interferon (IFNG; <a href="/entry/147570">147570</a>) production compared with their wildtype littermates. All Sap-deficient mice died as a result of hepatotropic LCMV infection, while only 30% of wildtype mice died. In contrast to the increased Ifng production, interleukin-4 (IL4; <a href="/entry/147780">147780</a>) production was markedly lower in Sap-deficient mice. Mice with a BALB/c background are normally highly susceptible to infection with the Leishmania major parasite due to poor Ifng production. However, Sap-deficient mice with a BALB/c background produced little Il4 and high levels of Ifng and had lower parasite burdens than wildtype BALB/c mice. This suggested that in the absence of SAP, IL4 gene activation is defective. Lower Il4 expression in Sap-deficient mice correlated with greatly reduced IgE production and reduced basal IgE expression. <a href="#39" class="mim-tip-reference" title="Wu, C., Nguyen, K. B., Pien, G. C., Wang, N., Gullo, C., Duncan, H., Sosa, M. R., Edwards, M. J., Borrow, P., Satoskar, A. R., Sharpe, A. H., Biron, C. A., Terhorst, C. <strong>SAP controls T cell responses to virus and terminal differentiation of T(H)2 cells.</strong> Nature Immun. 2: 410-414, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11323694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11323694</a>] [<a href="https://doi.org/10.1038/87713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11323694">Wu et al. (2001)</a> proposed that the Sap-deficient mouse model would be a useful tool for dissecting the complex XLP phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11323694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Czar, M. J., Kersh, E. N., Mijares, L. A., Lanier, G., Lewis, J., Yap, G., Chen, A., Sher, A., Duckett, C. S., Ahmed, R., Schwartzberg, P. L. <strong>Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP.</strong> Proc. Nat. Acad. Sci. 98: 7449-7454, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11404475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11404475</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11404475[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/10.1073/pnas.131193098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11404475">Czar et al. (2001)</a> introduced a targeted mutation into the Sh2d1a gene of mice. Mice deficient in SLAM-associated protein had normal lymphocyte development, but on challenge with infectious agents, recapitulated features of XLP. Infection with lymphocytic choriomeningitis virus or Toxoplasma gondii was associated with increased T-cell activation and interferon-gamma production, as well as a reduction of immunoglobulin-secreting cells. Anti-CD3-stimulated splenocytes from uninfected mutant mice produced increased IFN-gamma and decreased IL4, findings supported by decreased serum IgE levels in vivo. The Th1 skewing of these animals suggested that cytokine misregulation may contribute to phenotypes associated with mutations of SH2D1A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11404475" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a Sap knockout mouse model, <a href="#7" class="mim-tip-reference" title="Crotty, S., Kersh, E. N., Cannons, J., Schwartzberg, P. L., Ahmed, R. <strong>SAP is required for generating long-term humoral immunity.</strong> Nature 421: 282-287, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529646</a>] [<a href="https://doi.org/10.1038/nature01318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12529646">Crotty et al. (2003)</a> found that Sap-deficient mice generated strong acute IgG antibody responses after lymphocytic choriomeningitis virus infection, but these titers rapidly waned and were accompanied by a paucity of long-lived plasma cells and memory B cells. Virus-specific memory CD4 (<a href="/entry/186940">186940</a>)-positive T cells were present in the Sap -/- mice. Histologic analysis demonstrated a severe reduction in the number and size of germinal centers. Using adoptive transfer and cell mixing experiments, <a href="#7" class="mim-tip-reference" title="Crotty, S., Kersh, E. N., Cannons, J., Schwartzberg, P. L., Ahmed, R. <strong>SAP is required for generating long-term humoral immunity.</strong> Nature 421: 282-287, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529646</a>] [<a href="https://doi.org/10.1038/nature01318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12529646">Crotty et al. (2003)</a> showed that the defect resided not in B cells but in the CD4-positive T cells of Sap-deficient mice. They concluded that SAP expression in CD4-positive T cells is essential for generating long-lived plasma cells and memory B cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12529646" 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="Morra, M., Barrington, R. A., Abadia-Molina, A. C., Okamoto, S., Julien, A., Gullo, C., Kalsy, A., Edwards, M. J., Chen, G., Spolski, R., Leonard, W. J., Huber, B. T., Borrow, P., Biron, C. A., Satoskar, A. R., Carroll, M. C., Terhorst, C. <strong>Defective B cell responses in the absence of SH2D1A.</strong> Proc. Nat. Acad. Sci. 102: 4819-4823, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15774582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15774582</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15774582[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/10.1073/pnas.0408681102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15774582">Morra et al. (2005)</a> found that mice lacking Sh2d1a had severely impaired primary and secondary responses of all Ig subclasses to specific antigens, even in the absence of viral infection. Fluorescence microscopy demonstrated that Sh2d1a was present in germinal centers in spleens of wildtype mice, but that germinal centers were absent in Sh2d1a-deficient mice after primary immunization. Adoptive transfer experiments showed that Sh2d1a expression was required in both B and T lymphocytes for responses to soluble T-dependent antigens. <a href="#14" class="mim-tip-reference" title="Morra, M., Barrington, R. A., Abadia-Molina, A. C., Okamoto, S., Julien, A., Gullo, C., Kalsy, A., Edwards, M. J., Chen, G., Spolski, R., Leonard, W. J., Huber, B. T., Borrow, P., Biron, C. A., Satoskar, A. R., Carroll, M. C., Terhorst, C. <strong>Defective B cell responses in the absence of SH2D1A.</strong> Proc. Nat. Acad. Sci. 102: 4819-4823, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15774582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15774582</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15774582[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/10.1073/pnas.0408681102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15774582">Morra et al. (2005)</a> proposed that, in the absence of SH2D1A, progressive dysgammaglobulinemia can occur in XLP patients without the involvement of EBV. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15774582" 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 2-photon intravital imaging, <a href="#22" class="mim-tip-reference" title="Qi, H., Cannons, J. L., Klauschen, F., Schwartzberg, P. L., Germain, R. N. <strong>SAP-controlled T-B cell interactions underlie germinal centre formation.</strong> Nature 455: 764-769, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18843362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18843362</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18843362[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18843362">Qi et al. (2008)</a> showed that Sap deficiency in mice selectively impaired the ability of Cd4-positive T cells to interact with B lymphocytes, but not dendritic cells. This selective defect resulted in diminished levels of contact-dependent T-cell help, even though these T cells possessed other characteristics of competent helper T cells. Sap -/- T cells also displayed impaired recruitment to and retention in nascent germinal centers. <a href="#22" class="mim-tip-reference" title="Qi, H., Cannons, J. L., Klauschen, F., Schwartzberg, P. L., Germain, R. N. <strong>SAP-controlled T-B cell interactions underlie germinal centre formation.</strong> Nature 455: 764-769, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18843362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18843362</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18843362[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18843362">Qi et al. (2008)</a> concluded that the germinal center defect arising from Sap deficiency is caused by the inability of T cells to interact and communicate with cognate B cells, while interaction of T cells with dendritic cells remains unaffected. They proposed that SLAM family members may have a role in T- and B-cell interactions, and <a href="#9" class="mim-tip-reference" title="Deenick, E. K., Tangye, S. G. <strong>Helpful T cells are sticky.</strong> Nature 455: 745 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18843357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18843357</a>] [<a href="https://doi.org/10.1038/455745a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18843357">Deenick and Tangye (2008)</a>, in a commentary, suggested that the SLAM family member CD84 (<a href="/entry/604513">604513</a>) is a promising candidate. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18843362+18843357" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a conditional gene targeting approach in mice and intracellular flow cytometric analysis, <a href="#38" class="mim-tip-reference" title="Veillette, A., Zhang, S., Shi, X., Dong, Z., Davidson, D., Zhong, M.-C. <strong>SAP expression in T cells, not in B cells, is required for humoral immunity.</strong> Proc. Nat. Acad. Sci. 105: 1273-1278, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18212118/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18212118</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18212118[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/10.1073/pnas.0710698105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18212118">Veillette et al. (2008)</a> showed that the defects in antibody production and memory B-cell generation in Sap-deficient mice, and presumably humans with XLP, resulted from lack of Sap expression in T cells, but not in B cells or NK cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18212118" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>14 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=300490[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs111033623 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033623;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=rs111033623" 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=rs111033623" 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=RCV000011645 OR RCV001091713 OR RCV001270156" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011645, RCV001091713, RCV001270156" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011645...</a>
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<p>In a patient with X-linked lymphoproliferative disease (<a href="/entry/308240">308240</a>), <a href="#6" class="mim-tip-reference" title="Coffey, A. J., Brooksbank, R. A., Brandau, O., Oohashi, T., Howell, G. R., Bye, J. M., Cahn, A. P., Durham, J., Heath, P., Wray, P., Pavitt, R., Wilkinson, J., and 31 others. <strong>Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.</strong> Nature Genet. 20: 129-135, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771704</a>] [<a href="https://doi.org/10.1038/2424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771704">Coffey et al. (1998)</a> identified a 462C-T transition in the SH2D1A gene, resulting in an arg55-to-ter (R55X) substitution in the middle of the SH2 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771704" 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 2 of 4 patients with XLP, <a href="#11" class="mim-tip-reference" title="Lappalainen, I., Giliani, S., Franceschini, R., Bonnefoy, J.-Y., Duckett, C., Notarangelo, L. D., Vihinen, M. <strong>Structural basis for SH2D1A mutations in X-linked lymphoproliferative disease.</strong> Biochem. Biophys. Res. Commun. 269: 124-130, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10694488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10694488</a>] [<a href="https://doi.org/10.1006/bbrc.2000.2146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10694488">Lappalainen et al. (2000)</a> identified the R55X mutation. They noted that the mutation involves a CpG dinucleotide and suggested that nucleotide 462 is a mutation hotspot in the SH2D1A gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10694488" 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">rs111033628 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033628;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=rs111033628" 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=rs111033628" 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=RCV000011646" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011646" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011646</a>
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<p>In a patient with XLP (<a href="/entry/308240">308240</a>), <a href="#6" class="mim-tip-reference" title="Coffey, A. J., Brooksbank, R. A., Brandau, O., Oohashi, T., Howell, G. R., Bye, J. M., Cahn, A. P., Durham, J., Heath, P., Wray, P., Pavitt, R., Wilkinson, J., and 31 others. <strong>Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.</strong> Nature Genet. 20: 129-135, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771704</a>] [<a href="https://doi.org/10.1038/2424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771704">Coffey et al. (1998)</a> identified a 471C-T transition in the SH2D1A cDNA, resulting in a gln58-to-ter (Q58X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771704" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
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SH2D1A, 159-BP DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011647" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011647" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011647</a>
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<p>In 2 brothers with XLP (<a href="/entry/308240">308240</a>), <a href="#6" class="mim-tip-reference" title="Coffey, A. J., Brooksbank, R. A., Brandau, O., Oohashi, T., Howell, G. R., Bye, J. M., Cahn, A. P., Durham, J., Heath, P., Wray, P., Pavitt, R., Wilkinson, J., and 31 others. <strong>Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.</strong> Nature Genet. 20: 129-135, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771704</a>] [<a href="https://doi.org/10.1038/2424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771704">Coffey et al. (1998)</a> identified a 159-bp deletion following nucleotide 448 of the SH2D1A gene, which removed a 3-prime 53 bp of exon 2 and the 5-prime 106 bp of intronic sequence. This deletion removed 18 amino acids from the center of the SH2 domain, as well as the donor splice site at the end of the exon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771704" 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">rs111033624 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033624;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=rs111033624" 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=rs111033624" 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=RCV000011648" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011648" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011648</a>
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<p>In a male with XLP (<a href="/entry/308240">308240</a>), <a href="#6" class="mim-tip-reference" title="Coffey, A. J., Brooksbank, R. A., Brandau, O., Oohashi, T., Howell, G. R., Bye, J. M., Cahn, A. P., Durham, J., Heath, P., Wray, P., Pavitt, R., Wilkinson, J., and 31 others. <strong>Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.</strong> Nature Genet. 20: 129-135, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771704</a>] [<a href="https://doi.org/10.1038/2424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771704">Coffey et al. (1998)</a> identified a 394G-C transversion in the SH2D1A gene, resulting in an arg32-to-thr (R32T) substitution. The presence of an arginine at position 32 in the SH2 domain is critical for phosphotyrosine binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771704" 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>.0005 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</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">rs1603238847 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1603238847;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=rs1603238847" 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=rs1603238847" 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=RCV000011649" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011649" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011649</a>
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<p>In 2 affected brothers with XLP (<a href="/entry/308240">308240</a>), <a href="#6" class="mim-tip-reference" title="Coffey, A. J., Brooksbank, R. A., Brandau, O., Oohashi, T., Howell, G. R., Bye, J. M., Cahn, A. P., Durham, J., Heath, P., Wray, P., Pavitt, R., Wilkinson, J., and 31 others. <strong>Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.</strong> Nature Genet. 20: 129-135, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771704</a>] [<a href="https://doi.org/10.1038/2424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771704">Coffey et al. (1998)</a> identified a 500G-T transversion in the SH2D1A gene. The change was in the last nucleotide of the exon, changing the splice site from AGgt to ATgt. RNA was not available; however, it was predicted that the mutation would inhibit correct splicing, as the mutation resulted in a reduction in the splice site score (<a href="#28" class="mim-tip-reference" title="Shapiro, M. B., Senapathy, P. <strong>RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression.</strong> Nucleic Acids Res. 15: 7155-7174, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3658675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3658675</a>] [<a href="https://doi.org/10.1093/nar/15.17.7155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3658675">Shapiro and Senapathy, 1987</a>) from 81.8 (normal) to 69.0. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3658675+9771704" 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">rs111033625 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033625;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=rs111033625" 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=rs111033625" 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=RCV000011650" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011650" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011650</a>
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<p>In a patient with XLP (<a href="/entry/308240">308240</a>), <a href="#6" class="mim-tip-reference" title="Coffey, A. J., Brooksbank, R. A., Brandau, O., Oohashi, T., Howell, G. R., Bye, J. M., Cahn, A. P., Durham, J., Heath, P., Wray, P., Pavitt, R., Wilkinson, J., and 31 others. <strong>Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.</strong> Nature Genet. 20: 129-135, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771704</a>] [<a href="https://doi.org/10.1038/2424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771704">Coffey et al. (1998)</a> identified a 684T-A transversion in the SH2D1A gene, changing the normal termination codon to an arginine (X129R), resulting in an addition of 12 amino acids to the C terminus of the protein. The authors suggested that the C-terminal extension disrupts the folding of the SH2 domain or interferes with the interaction between the SH2 domain and its phosphotyrosine target. Alternatively, this mutation may disrupt an as yet unknown function of the normal C-terminal tail of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771704" 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 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
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SH2D1A, PRO101LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs111033626 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033626;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=rs111033626" 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=rs111033626" 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=RCV000011651" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011651" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011651</a>
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<p>In a patient with XLP (<a href="/entry/308240">308240</a>), <a href="#6" class="mim-tip-reference" title="Coffey, A. J., Brooksbank, R. A., Brandau, O., Oohashi, T., Howell, G. R., Bye, J. M., Cahn, A. P., Durham, J., Heath, P., Wray, P., Pavitt, R., Wilkinson, J., and 31 others. <strong>Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.</strong> Nature Genet. 20: 129-135, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771704</a>] [<a href="https://doi.org/10.1038/2424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771704">Coffey et al. (1998)</a> identified a 601C-T transition in the SH2D1A gene, resulting in a pro101-to-leu (P101L) amino acid substitution. The mutation was also demonstrated in 2 obligate carriers in the kindred. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771704" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
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SH2D1A, THR68ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs111033627 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033627;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=rs111033627" 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=rs111033627" 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=RCV000011652" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011652" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011652</a>
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<p>In a patient with XLP (<a href="/entry/308240">308240</a>), <a href="#6" class="mim-tip-reference" title="Coffey, A. J., Brooksbank, R. A., Brandau, O., Oohashi, T., Howell, G. R., Bye, J. M., Cahn, A. P., Durham, J., Heath, P., Wray, P., Pavitt, R., Wilkinson, J., and 31 others. <strong>Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.</strong> Nature Genet. 20: 129-135, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771704</a>] [<a href="https://doi.org/10.1038/2424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771704">Coffey et al. (1998)</a> identified a 502C-T transition in the SH2D1A gene, resulting in a thr68-to-ile (T68I) amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771704" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</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">rs1603236465 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1603236465;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=rs1603236465" 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=rs1603236465" 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=RCV000011653" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011653" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011653</a>
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<p>In a patient with XLP (<a href="/entry/308240">308240</a>), <a href="#6" class="mim-tip-reference" title="Coffey, A. J., Brooksbank, R. A., Brandau, O., Oohashi, T., Howell, G. R., Bye, J. M., Cahn, A. P., Durham, J., Heath, P., Wray, P., Pavitt, R., Wilkinson, J., and 31 others. <strong>Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.</strong> Nature Genet. 20: 129-135, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771704</a>] [<a href="https://doi.org/10.1038/2424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9771704">Coffey et al. (1998)</a> identified a C-to-T transition of position -10 in the promoter region of the SH2D1A gene, changing a potential CCAAT box to CTAAT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771704" 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>.0010 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
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SH2D1A, EX1DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011654" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011654" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011654</a>
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<p>In 2 brothers with XLP (<a href="/entry/308240">308240</a>) who presented with B-cell non-Hodgkin lymphoma without evidence of Epstein-Barr virus infection, <a href="#4" class="mim-tip-reference" title="Brandau, O., Schuster, V., Weiss, M., Hellebrand, H., Fink, F. M., Kreczy, A., Friedrich, W., Strahm, B., Niemeyer, C., Belohradsky, B. H., Meindl, A. <strong>Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP).</strong> Hum. Molec. Genet. 8: 2407-2413, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10556288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10556288</a>] [<a href="https://doi.org/10.1093/hmg/8.13.2407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10556288">Brandau et al. (1999)</a> and <a href="#30" class="mim-tip-reference" title="Strahm, B., Rittweiler, K., Duffner, U., Brandau, O., Orlowska-Volk, M., Karajannis, M. A., zur Stadt, U., Tiemann, M., Reiter, A., Brandis, M., Meindl, A., Niemeyer, C. M. <strong>Recurrent B-cell non-Hodgkin's lymphoma in two brothers with X-linked lymphoproliferative disease without evidence for Epstein-Barr virus infection.</strong> Brit. J. Haemat. 108: 377-382, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10691868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10691868</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2000.01884.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10691868">Strahm et al. (2000)</a> identified a deletion in the first exon of the SH2D1A gene. The brothers presented at ages 4 and 2 years, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10556288+10691868" 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">rs111033629 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033629;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=rs111033629" 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=rs111033629" 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=RCV000011655" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011655" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011655</a>
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<p>In a family with multiple XLP (<a href="/entry/308240">308240</a>) deaths from fulminant hepatitis or leukemia after EBV infection, <a href="#19" class="mim-tip-reference" title="Parolini, S., Bottino, C., Falco, M., Augugliaro, R., Giliani, S., Franceschini, R., Ochs, H. D., Wolf, H., Bonnefoy, J.-Y., Biassoni, R., Moretta, L., Notarangelo, L. D., Moretta, A. <strong>X-linked lymphoproliferative disease: 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells.</strong> J. Exp. Med. 192: 337-346, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10934222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10934222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10934222[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.192.3.337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10934222">Parolini et al. (2000)</a> identified a G-to-T transversion at nucleotide 3 in the translation initiation codon of the SH2D1A gene, resulting in a met1-to-ile substitution. The mutation was demonstrated in a healthy 3-year-old and in obligate carriers in the kindred. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10934222" 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>.0012 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
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SH2D1A, 163C-T
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011645 OR RCV001091713 OR RCV001270156" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011645, RCV001091713, RCV001270156" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011645...</a>
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<p>In a patient with XLP (<a href="/entry/308240">308240</a>) and in his 2 asymptomatic nephews, <a href="#19" class="mim-tip-reference" title="Parolini, S., Bottino, C., Falco, M., Augugliaro, R., Giliani, S., Franceschini, R., Ochs, H. D., Wolf, H., Bonnefoy, J.-Y., Biassoni, R., Moretta, L., Notarangelo, L. D., Moretta, A. <strong>X-linked lymphoproliferative disease: 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells.</strong> J. Exp. Med. 192: 337-346, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10934222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10934222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10934222[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.192.3.337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10934222">Parolini et al. (2000)</a> identified a 163C-to-T transition in the SH2D1A gene, leading to a premature termination at codon 55. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10934222" 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>.0013 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
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SH2D1A, ARG55LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs111033630 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033630;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=rs111033630" 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=rs111033630" 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=RCV000011657" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011657" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011657</a>
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<p><a href="#3" class="mim-tip-reference" title="Benoit, L., Wang, X., Pabst, H. F., Dutz, J., Tan, R. <strong>Cutting edge: defective NK cell activation in X-linked lymphoproliferative disease.</strong> J. Immun. 165: 3549-3553, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11034354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11034354</a>] [<a href="https://doi.org/10.4049/jimmunol.165.7.3549" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11034354">Benoit et al. (2000)</a> identified an arg55-to-leu mutation in the second exon of the SH2D1A gene in autopsy specimens from 2 maternally related cousins diagnosed with XLP (<a href="/entry/308240">308240</a>). They also identified the mutation in 2 healthy, EBV-seronegative males in the extended family. Based on the molecular structure of the SH2D1A-SLAM (<a href="/entry/603492">603492</a>) interaction, this mutation was predicted to disrupt binding between the SH2 domain of SH2D1A and the cytoplasmic domain of SLAM. The mutation was also predicted to interfere with SH2D1A-2B4 (<a href="/entry/605554">605554</a>) binding because of the strong amino acid homology shared by SLAM and 2B4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11034354" 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>.0014 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
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SH2D1A, IVS1DS, G-C, +5
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777612 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777612;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=rs587777612" 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=rs587777612" 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=RCV000133459" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000133459" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000133459</a>
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<p><a href="#23" class="mim-tip-reference" title="Recher, M., Fried, A. J., Massaad, M. J., Kim, H. Y., Rizzini, M., Frugoni, F., Walter, J. E., Mathew, D., Eibel, H., Hess, C., Giliani, S., Umetsu, D. T., Notarangelo, L. D., Geha, R. S. <strong>Intronic SH2D1A mutation with impaired SAP expression and agammaglobulinemia.</strong> Clin. Immun. 146: 84-89, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23280491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23280491</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23280491[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.clim.2012.11.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23280491">Recher et al. (2013)</a> reported a 2-year-old Caucasian boy of nonconsanguineous parents who developed recurrent suppurative otitis media at 8 months of age followed by other bacterial and viral, but not EBV, infections. At 13 months of age, no serum IgG, IgA, or IgM was detectable, and B-cell levels were below normal. At 17 and 24 months of age, IgA and IgM remained undetectable, but B-cell numbers were within normal range. NKT cells were undetectable. At 3 years of age, EBV viremia was found as part of a pre-bone marrow transplant evaluation, but it remained clinically silent and resolved after B-cell depleting therapy. Sequencing of the SH2D1A gene revealed a G-C transversion at position +5 in intron 1. Patient SH2D1A mRNA was of normal length and sequence, but its expression was reduced 10-fold compared with a healthy control. Western blot analysis showed reduced expression of a normal-sized SH2D1A protein. Flow cytometric analysis demonstrated virtual abrogation of SH2D1A expression. Sequence analysis of the parental SH2D1A genes revealed the mother to be the carrier of the mutation, with wildtype sequence in the father. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23280491" 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="#Scher1982" class="mim-tip-reference" title="Scher, I. <strong>The CBA/N mouse strain: an experimental model illustrating the influence of the X-chromosome on immunity.</strong> Adv. Immun. 33: 1-71, 1982.">Scher (1982)</a>
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<strong>REFERENCES</strong>
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<a id="Aoukaty2005" class="mim-anchor"></a>
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Aoukaty, A., Tan, R.
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<strong>Role for glycogen synthase kinase-3 in NK cell cytotoxicity and X-linked lymphoproliferative disease.</strong>
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J. Immun. 174: 4551-4558, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15814676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15814676</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15814676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.4049/jimmunol.174.8.4551" target="_blank">Full Text</a>]
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Arico, M., Imashuku, S., Clementi, R., Hibi, S., Teramura, T., Danesino, C., Haber, D. A., Nichols, K. E.
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<strong>Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene.</strong>
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Blood 97: 1131-1133, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159547</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11159547" 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/10.1182/blood.v97.4.1131" target="_blank">Full Text</a>]
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Benoit, L., Wang, X., Pabst, H. F., Dutz, J., Tan, R.
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<strong>Cutting edge: defective NK cell activation in X-linked lymphoproliferative disease.</strong>
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J. Immun. 165: 3549-3553, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11034354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11034354</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11034354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.4049/jimmunol.165.7.3549" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/8.13.2407" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ncb920" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/2424" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature01318" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.131193098" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/455745a" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/emboj/21.3.314" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/bbrc.2000.2146" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/90615" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M206649200" target="_blank">Full Text</a>]
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<a id="35" class="mim-anchor"></a>
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<a id="Tangye1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tangye, S. G., Lazetic, S., Woollatt, E., Sutherland, G. R., Lanier, L. L., Phillips, J. H.
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<strong>Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP.</strong>
|
|
J. Immun. 162: 6981-6985, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10358138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10358138</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10358138" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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<a id="36" class="mim-anchor"></a>
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<a id="Tangye2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tangye, S. G., Phillips, J. H., Lanier, L. L., Nichols, K. E.
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|
<strong>Cutting edge: functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome.</strong>
|
|
J. Immun. 165: 2932-2936, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10975798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10975798</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10975798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.4049/jimmunol.165.6.2932" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="37" class="mim-anchor"></a>
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<a id="Thorley-Lawson1982" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thorley-Lawson, D. A., Schooley, R. T., Bhan, A. K., Nadler, L. M.
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<strong>Epstein-Barr virus superinduces a new human B cell differentiation antigen (B-LAST 1) expressed on transformed lymphoblasts.</strong>
|
|
Cell 30: 415-425, 1982.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6291768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6291768</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6291768" 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(82)90239-2" target="_blank">Full Text</a>]
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<li>
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<a id="38" class="mim-anchor"></a>
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<a id="Veillette2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Veillette, A., Zhang, S., Shi, X., Dong, Z., Davidson, D., Zhong, M.-C.
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<strong>SAP expression in T cells, not in B cells, is required for humoral immunity.</strong>
|
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Proc. Nat. Acad. Sci. 105: 1273-1278, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18212118/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18212118</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18212118[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=18212118" 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/10.1073/pnas.0710698105" target="_blank">Full Text</a>]
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</p>
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<a id="39" class="mim-anchor"></a>
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<a id="Wu2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wu, C., Nguyen, K. B., Pien, G. C., Wang, N., Gullo, C., Duncan, H., Sosa, M. R., Edwards, M. J., Borrow, P., Satoskar, A. R., Sharpe, A. H., Biron, C. A., Terhorst, C.
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<strong>SAP controls T cell responses to virus and terminal differentiation of T(H)2 cells.</strong>
|
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Nature Immun. 2: 410-414, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11323694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11323694</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11323694" 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/10.1038/87713" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="40" class="mim-anchor"></a>
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<a id="Yin1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yin, L., Ferrand, V., Lavoue, M.-F., Hayoz, D., Philippe, N., Souillet, G., Seri, M., Giacchino, R., Castagnola, E., Hodgson, S., Sylla, B. S., Romeo, G.
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<strong>SH2D1A mutation analysis for diagnosis of XLP in typical and atypical patients.</strong>
|
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Hum. Genet. 105: 501-505, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10598819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10598819</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10598819" 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/s004390051137" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="41" class="mim-anchor"></a>
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<a id="Yin1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yin, L., Tocco, T., Pauly, S., Lenoir, G. M., Romeo, G.
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<strong>Absence of SH2D1A point mutation in 62 Burkitts lymphoma cell lines.</strong>
|
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Am. J. Hum. Genet. 65 (suppl. 1868): A331 only, 1999.
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</p>
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</div>
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</ol>
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<div>
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<br />
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<a id="contributors" class="mim-anchor"></a>
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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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Paul J. Converse - updated : 9/16/2013
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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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Patricia A. Hartz - updated : 1/21/2011<br>Paul J. Converse - updated : 8/30/2010<br>Paul J. Converse - updated : 11/19/2008<br>Paul J. Converse - updated : 3/12/2008<br>Paul J. Converse - updated : 8/31/2007<br>Paul J. Converse - updated : 10/20/2006<br>Paul J. Converse - updated : 10/17/2006<br>Paul J. Converse - updated : 9/19/2006<br>Marla J. F. O'Neill - updated : 3/29/2005<br>Victor A. McKusick - updated : 3/21/2005<br>Paul J. Converse - updated : 6/18/2004
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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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Cassandra L. Kniffin : 4/5/2004
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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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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alopez : 08/19/2014
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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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mgross : 9/16/2013<br>mgross : 9/16/2013<br>mgross : 2/9/2011<br>terry : 1/21/2011<br>mgross : 10/4/2010<br>terry : 8/30/2010<br>mgross : 11/19/2008<br>terry : 11/19/2008<br>mgross : 3/13/2008<br>terry : 3/12/2008<br>mgross : 10/29/2007<br>mgross : 10/29/2007<br>terry : 8/31/2007<br>alopez : 1/16/2007<br>mgross : 10/20/2006<br>mgross : 10/20/2006<br>terry : 10/17/2006<br>mgross : 9/20/2006<br>terry : 9/19/2006<br>terry : 8/3/2005<br>wwang : 3/30/2005<br>wwang : 3/29/2005<br>alopez : 3/24/2005<br>terry : 3/21/2005<br>carol : 10/1/2004<br>mgross : 6/18/2004<br>carol : 5/26/2004<br>carol : 5/26/2004<br>carol : 5/26/2004<br>ckniffin : 4/14/2004
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 300490
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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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SH2 DOMAIN PROTEIN 1A; SH2D1A
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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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SIGNALING LYMPHOCYTE ACTIVATION MOLECULE-ASSOCIATED PROTEIN<br />
|
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SLAM-ASSOCIATED PROTEIN; SAP
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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: SH2D1A</em></strong>
|
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1162828001;
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</span>
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</p>
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<div>
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<br />
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</div>
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<div>
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<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: Xq25
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Genomic coordinates <span class="small">(GRCh38)</span> : X:124,346,563-124,373,160 </span>
|
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</em>
|
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</strong>
|
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<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
|
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<span class="mim-font">
|
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Xq25
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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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Lymphoproliferative syndrome, X-linked, 1
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
308240
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
X-linked recessive
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
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>
|
|
</span>
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</h4>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Cloning and Expression</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>By positional cloning, Coffey et al. (1998) identified the gene mutated in X-linked lymphoproliferative disease (XLP; 308240). The SH2 domain protein-1A (SH2D1A) gene encodes a deduced 128-amino acid protein consisting of a 5-amino acid N-terminal sequence, an SH2 domain, and a 25-amino acid C-terminal tail. The absence of a hydrophobic signal sequence suggests that SH2D1A is localized in the cytoplasm. Northern blot analysis detected a 2.5-kb SH2D1A mRNA expressed at high levels in thymus and lung, with a lower level of expression in spleen and liver. SH2D1A expression was also detected by RT-PCR in all lymphocyte populations assayed, but was not detected in a range of EBV-transformed lymphoblastoid cell lines. </p><p>To determine the signaling mechanism of SLAM (signaling lymphocyte activation molecule; 603492), a glycosylated transmembrane protein also known as CDw150 or CD150, Sayos et al. (1998) identified the SH2D1A gene, which they referred to as SAP for 'SLAM-associated protein.' The predicted 128-amino acid human SAP protein is 96% homologous to the murine protein in both the SH2 and tail domains. In both humans and in mice, SAP is expressed in all major subsets of T cells, including CD4+, CD45RO+, CD45RA+, and CD8+, but not in B 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>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Coffey et al. (1998) determined that the SH2D1A gene contains 4 exons. </p>
|
|
</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>Mapping</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
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<p>By positional cloning, Coffey et al. (1998) identified the SH2D1A gene within the X-linked lymphoproliferative disease critical region on Xq25. Using a clone that contained all 4 exons of mouse Sap, Sayos et al. (1998) localized the gene to the part of the mouse X chromosome corresponding to human Xq25. </p>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</h4>
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<span class="mim-text-font">
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<p>Lappalainen et al. (2000) developed a 3-dimensional model of the SH2 domain of the SH2D1A protein. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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<p>SLAM is a protein that is centrally involved in the bidirectional stimulation of T and B cells. When activated, it mediates expansion of activated T cells during immune responses, induces production of interferon-gamma, and changes the functional profile of subsets of T cells. Signaling through SLAM-SLAM binding during mutual interaction between B cells, and between B cells and T cells, increases the expansion and differentiation of activated B cells. Sayos et al. (1998) found that SAP binding blocks the recruitment of the tyrosine phosphatase SHP2 (176876) to the phosphorylated cytoplasmic domain of SLAM, suggesting that SAP is a natural inhibitor of SLAM. Upon T-cell activation, SLAM may switch from a signaling cascade that is dependent on SAP, and probably on FYN (137025), a member of the src tyrosine kinase family, to one that depends on SHP2. Sayos et al. (1998) proposed that SAP controls the signal-transduction pathways initiated by interactions between SLAM molecules at the interface between T and B cells. Sayos et al. (1998) showed that SAP cDNAs isolated from the blood cells of patients with X-linked lymphoproliferative syndrome did not bind SLAM. </p><p>Poy et al. (1999) described 3-dimensional protein structures showing that SH2D1A binds phosphorylated and nonphosphorylated SLAM peptides in a similar mode, with the tyrosine- or phosphotyrosine-281 residue inserted into the phosphotyrosine-binding pocket. Specific interactions with residues N-terminal to this tyrosine, in addition to more characteristic C-terminal interactions, stabilize the complexes. SH2D1A interacts via its SH2 domain with the protein sequence motif TIpYXX(V/I). A phosphopeptide library screen and analysis of mutations identified in XLP patients confirmed that these extended interactions are required for SH2D1A function. </p><p>Using binding analysis, Tangye et al. (1999) found that phosphorylated 2B4 (605554), a protein with significant homology to SLAM, recruits either SHP2 or SAP. </p><p>Sylla et al. (2000) reported that SH2D1A associates with DOK1 (602919), a protein that interacts with RAS-GAP, cytoplasmic tyrosine kinase (CSK; 124095), and NCK (see NCK1; 600508). They found that an SH2D1A SH domain mutant found in XLP does not associate with Dok1, suggesting this interaction is linked to XLP. Other evidence indicated that SH2D1A can affect multiple intracellular signaling pathways that are potentially important in the normal effective host response to Epstein-Barr virus (EBV) infection. </p><p>Morra et al. (2001) stated that SH2D1A interacts via its SH2 domain with a motif (TIYXXV) present in the cytoplasmic tail of the cell-surface receptors CD150 (SLAM), CD84 (604513), CD229 (LY9; 600684), and CD244 (2B4). Morra et al. (2001) analyzed the effect of SH2D1A protein missense mutations identified in 10 XLP families and found that the mutant proteins clustered into 2 major groups: mutants with a markedly decreased half-life, and mutants with structural changes that variably affect their interaction with the 4 receptors. Because there was no correlation between the type of mutation and clinical presentation, Morra et al. (2001) concluded that unidentified genetic or environmental factors must play a strong role in XLP disease manifestations. </p><p>Hwang et al. (2002) screened a repertoire of synthetic peptides and stated that the consensus motif for binding is T/SXXXXV/I. This motif is unusual in that it contains neither a tyrosine nor a phosphotyrosine residue, hallmarks of conventional SH2 domain-ligand interactions. The NMR-determined structures of the protein in complex with 2 distinct peptides provided direct evidence in support of a '3-pronged,' more versatile, binding mechanism for the SH2D1A SH2 domain, in contrast to the '2-pronged' binding for conventional SH2 domains. Hwang et al. (2002) noted that all of the mutants examined in their study showed markedly reduced affinities for the nonphosphorylated SLAM peptide, suggesting that phosphorylation-independent interactions mediated by SH2D1A likely play an important role in the pathogenesis of XLP. </p><p>Using an array of peptides derived from the SLAM family of receptors, Li et al. (2003) demonstrated that SH2D1A binds with comparable affinities to the same sites in those receptors as do the SH2 domains of SHP2 and SH2-containing inositol phosphatase (SHIP; 601582), suggesting that the 3 proteins may compete against one another in binding to a given SLAM family receptor. Furthermore, in vitro and in vivo binding studies indicated that SH2D1A is capable of binding directly to the T cell-specific tyrosine kinase FYN (137025), an interaction mediated by the FYN SH3 domain. In cells, FYN was shown to be indispensable for SLAM tyrosine phosphorylation, which, in turn, was dramatically enhanced by SH2D1A. Because SH2D1A also blocked the recruitment of SHP2 to SLAM, Li et al. (2003) proposed a dual functional role for SH2D1A in SLAM signaling, acting as both an adaptor for FYN and an inhibitor to SHP2 binding. They concluded that this dual role is likely to be physiologically relevant, since disease-causing SH2D1A mutants exhibited significantly reduced affinities to both FYN and SLAM. </p><p>The cytoplasmic protein encoded by the SH2D1A gene plays an essential role in controlling EBV infection. It is expressed in T and NK cells, but not in B cells or in granulocytes. Parolini et al. (2003) tested the hypothesis that DNA methylation contributes to tissue-specific SH2D1A gene expression and analyzed the methylation status of 2,300 bp upstream of the ATG starting codon, the coding region, and part of intron 1. By bisulfite sequencing and methylation-sensitive restriction enzyme digestion, they showed that a differential methylation pattern of CpG-rich regions in the 5-prime region and the adjacent exon 1 of the SH2D1A gene indeed correlates with the tissue-specific gene transcription. </p><p>By studying NK-cell function in patients with XLP and a defect in the SAP gene, Parolini et al. (2000) found that a number of triggering receptors displayed normal function. However, upon 2B4 interaction with CD48 (109530), NK-cell function against EBV-infected cells, which is primarily mediated via NKp46 (LY94; 604530), was inhibited. Disruption of 2B4-CD48 and/or NK receptor-HLA interaction restored NK cytolytic activity. RT-PCR analysis detected the full-length 2B4 cDNA as well as a 2B4 molecule lacking the Ig C2 domain in both patients and normal individuals. Molecular analysis failed to reveal any differences between normal and patient 2B4 sequences. Immunoblot analysis showed that treatment of normal but not XLP NK cells with pervanadate led to the association of 2B4 with SAP. Parolini et al. (2000) suggested that anti-2B4 treatment might be of use in XLPD patients awaiting bone marrow transplantation. Tangye et al. (2000) found that although XLP patient NK cells can be active, the absence of SAP selectively cripples the 2B4-mediated activation pathway. XLPD patient NK cells were unable to lyse CD48-expressing target cells. The authors pointed out that CD48 was originally identified as an antigen whose expression is at least 10-fold greater on EBV-transformed cells than on EBV-negative cells (Thorley-Lawson et al., 1982). </p><p>Aoukaty and Tan (2005) found that NK cells from individuals with XLP due to SAP mutations failed to phosphorylate GSK3A (606784) and GSK3B (605004) after stimulation of 2B4. Lack of GSK3 phosphorylation inactivated GSK3 and prevented accumulation of the transcriptional coactivator beta-catenin (CTNNB1; 116806) in the cytoplasm and its subsequent translocation to the nucleus. Aoukaty and Tan (2005) identified VAV1 (164875), RAC1 (602048), RAF1 (164760), MEK2 (MAP2K2; 601263), ERK1 (MAPK3; 601795), and ERK3 (MAPK6; 602904) as proteins potentially involved in mediating the signaling pathway between 2B4 and GSK3/CTNNB and found that some of these elements were aberrant in XLP NK cells. Aoukaty and Tan (2005) concluded that GSK3 and beta-catenin mediate signaling of 2B4 in NK cells and that dysfunction of some of the elements in the transduction pathway between 2B4 and GSK3/beta-catenin may result in diminished IFNG (147570) secretion and cytotoxic function of NK cells in XLP patients. </p><p>Latour et al. (2001) reported that antibody-mediated ligation of SLAM on thymocytes triggered a protein tyrosine phosphorylation signal in T cells in a SAP-dependent manner. This signal also involved SHIP; the adaptor molecules DOK2 (604997), DOK1, and SHC (600560); and RASGAP (see 139150). SAP was crucial for this pathway because it selectively recruited and activated the T-cell isoform of FYN. </p><p>Sanzone et al. (2003) showed that T cells from patients with XLP were deficient in expression of the activation marker CD25 (IL2RA; 147730) and in IL2 (147680) production in response to T-cell receptor (TCR) stimulation, but not in response to TCR-independent stimulation by phorbol ester. The activation deficiency was associated with diminished VAV and MAP kinase phosphorylation, and it could be reversed by retroviral-mediated SAP gene transfer. </p><p>Using yeast 2-hybrid, immunoblot, and structural analyses, Chan et al. (2003) showed that the SH2 domain of SAP bound to the SH3 domain of FYN in a noncanonical manner and directly coupled FYN to SLAM. </p><p>Nichols et al. (2005) observed that Sh2d1a -/- mice lacked NKT cells in the thymus and peripheral organs. The defect in NKT cell ontogeny was hematopoietic cell-autonomous and could be rescued by reconstitution of Sh2d1a expression within Sh2d1a -/- bone marrow cells. Nichols et al. (2005) also studied 17 individuals with XLP and differing SH2D1A genotypes. All 17 lacked NKT cells, and a female XLP carrier showed completely skewed X chromosome inactivation within NKT cells, but not T or B cells. Nichols et al. (2005) concluded that SH2D1A is a crucial regulator of NKT cell ontogeny, and that the absence of NKT cells may contribute to the XLP phenotype, including abnormal antiviral and antitumor immunity and hypogammaglobulinemia. </p><p>Independently, Pasquier et al. (2005) showed that SAP was required for NKT cell development in mice and humans. They proposed that NKT cells may be important in the immune response to EBV. </p><p>By studying TCR restimulation of preactivated T cells from EBV-naive XLP patients after prolonged exposure to IL2, Snow et al. (2009) found that activated T cells from these patients were specifically and substantially less sensitive to restimulation-induced cell death (RICD). Silencing SAP or NTBA (SLAMF6; 606446) expression recapitulated resistance to RICD in normal T cells, indicating that both molecules are necessary for optimal TCR-induced apoptosis. TCR restimulation triggered increased recruitment of SAP to NTBA, and these proteins functioned to augment TCR-induced signal strength and induction of downstream proapoptotic target genes, including FASL (TNFSF6; 134638) and BIM (BCL2L11; 603827). Snow et al. (2009) proposed that XLP patients are inherently susceptible to antigen-induced lymphoproliferative disease and fulminant infectious mononucleosis due to compromised RICD. </p><p>Nagy et al. (2009) found that p53 (TP53; 191170) was upregulated in activated T cells, and they had previously shown that p53 induces SAP expression in lymphoid cells. Expression of SAP in the Saos-2 human osteosarcoma cell line, which lacks p53, was required to control cell proliferation after irradiation-induced DNA damage. High SAP expression rendered T-ALL tumor cell lines more sensitive to activation-induced cell death, and lymphoblastic cell lines developed from healthy donors, but not those from XLP patients, arrested in G2/M phase of the cell cycle following irradiation. Nagy et al. (2009) concluded that SAP may be involved in the termination of T-cell responses via activation-induced cell death. They proposed that the absence of functional SAP in XLP patients may allow extended survival of overactivated T cells in infectious mononucleosis, leading to the massive tissue infiltrates and organ failures seen in fatal infectious mononucleosis. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 9 unrelated patients with X-linked lymphoproliferative syndrome, Coffey et al. (1998) identified mutations in the SH2D1A gene (300490.0001-300490.0009). </p><p>Sumegi et al. (1999) reviewed the molecular basis of Duncan disease and tabulated 15 mutations in the SH2D1A gene. In 2 brothers with early-onset non-Hodgkin lymphoma, but no clinical or laboratory evidence of EBV infection, Brandau et al. (1999) identified a deletion of exon 1 of the SH2D1A gene (300490.0010). Other SH2D1A mutations were identified in 2 additional unrelated patients without evidence of EBV infection; 1 had non-Hodgkin lymphoma and 1 had signs of dysgammaglobulinemia. Development of dysgammaglobulinemia and lymphoma without evidence of prior EBV infection in 4 patients suggested that EBV is unrelated to these particular phenotypes, in contrast to fulminant or fatal infectious mononucleosis. No SH2D1A mutations were found in 3 families in which clinical features were suggestive of XLP. </p><p>By PCR, RT-PCR, and sequence analysis of genetic material from 19 typical and 8 atypical XLP patients, Yin et al. (1999) identified 13 mutations in the SH2D1A gene. One atypical patient reported by Yin et al. (1999) had initially been diagnosed as having B-cell leukemia, and the diagnosis of XLP was ascertained only after detection of an SH2D1A mutation in the patient's genomic DNA. Brandau et al. (1999) had identified mutations in the SH2D1A gene in 2 independent B-cell leukemia patients. However, Yin et al. (1999) concluded that the experience in their atypical XLP patient and the negative result of mutation screening in 62 Burkitt lymphoma cell lines (Yin et al., 1999) seemed to exclude SH2D1A mutations as causative in B-cell leukemia. Strahm et al. (2000) described 2 brothers, previously reported by Brandau et al. (1999), suffering from recurrent manifestations of B-cell non-Hodgkin lymphoma and recurrent infections of the lower respiratory tract associated with bronchiectasis. Molecular analysis of the SH2D1A gene led to the identification of a deletion in the first exon (300490.0010) in both patients. Strahm et al. (2000) postulated that the genetic defect identified in the 2 EBV-seronegative brothers with non-Hodgkin lymphoma (300490.0010) resulted in a dysregulation of the B-/T-cell interaction, rendering these patients susceptible to the early onset of B-cell non-Hodgkin lymphoma. </p><p>Using an SSCP assay for mutation analysis, Lappalainen et al. (2000) identified mutations in the SH2D1A gene in 4 patients with a clinical history of XLP. Noting that a large proportion of SH2D1A mutations lead to truncation of the produced protein, the authors used molecular modeling to show that truncated SH2D1A proteins do not fold and function correctly even if produced. </p><p>Sumegi et al. (2000) reported that analysis of 35 families from the XLP Registry revealed 28 different mutations in 34 families: 3 large genomic deletions, 10 small intragenic deletions, 3 splice site, 3 nonsense, and 9 missense mutations. No mutations were found in 25 males, so-called sporadic XLP (males with an XLP phenotype after EBV infection but no family history of XLP), or in 9 patients with chronic active EBV syndrome. The authors found that although EBV infection often resulted in fulminant infectious mononucleosis, it was not necessary for the expression of other manifestations of XLP and correlated poorly with outcome. They interpreted the results as suggesting that unidentified factors, either environmental or genetic (e.g., modifier genes), contribute to the pathogenesis of XLP. </p><p>The phenotype of hemophagocytic lymphohistiocytosis (HPLH; 267700) bears a strong resemblance to X-linked lymphoproliferative disease. For that reason, Arico et al. (2001) analyzed 25 patients diagnosed with HPLH for germline mutations in the SH2D1A gene. They identified 4 patients who had XLP and a mutation in the SH2D1A gene. Two had hemizygous deletions encompassing SH2D1A exon 1 (300490.0010) and 2 had nonsense mutations. Among these 4 patients, only 2 had family histories consistent with XLP. </p><p>Sumazaki et al. (2001) searched for mutations in the SH2D1A gene in 40 males in Japan who presented with severe EBV-associated illnesses, including fulminant infectious mononucleosis, EBV-positive lymphoma, and severe chronic active EBV infection. SH2D1A mutations were detected in 10 of the patients; 5 of these 10 were sporadic cases. Patients with SH2D1A mutations displayed severe acute infectious mononucleosis with hyperimmunoglobulin M, hypogammaglobulinemia, and B-cell malignant lymphoma. In contrast, chronic active EBV infection was not associated with SH2D1A mutations. </p><p>Ross et al. (2005) pointed out that discovery of the relationship between X-linked lymphoproliferative disease and the SH2D1A gene is an example of how the identification of genes involved in rare conditions can yield important biologic insights. In this instance, discovery of mutations in the SH2D1A gene led to identification of a new mediator of signal transduction between T and NK cells, and a novel family of proteins involved in the regulation of the immune response. </p>
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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>Wu et al. (2001) generated Sap-deficient mice, which were fertile and had no defects in lymphocyte surface markers or overall morphology. Sap-deficient mice had increased lymphocytic choriomeningitis virus (LCMV)-specific splenic and hepatic T cells and increased gamma-interferon (IFNG; 147570) production compared with their wildtype littermates. All Sap-deficient mice died as a result of hepatotropic LCMV infection, while only 30% of wildtype mice died. In contrast to the increased Ifng production, interleukin-4 (IL4; 147780) production was markedly lower in Sap-deficient mice. Mice with a BALB/c background are normally highly susceptible to infection with the Leishmania major parasite due to poor Ifng production. However, Sap-deficient mice with a BALB/c background produced little Il4 and high levels of Ifng and had lower parasite burdens than wildtype BALB/c mice. This suggested that in the absence of SAP, IL4 gene activation is defective. Lower Il4 expression in Sap-deficient mice correlated with greatly reduced IgE production and reduced basal IgE expression. Wu et al. (2001) proposed that the Sap-deficient mouse model would be a useful tool for dissecting the complex XLP phenotypes. </p><p>Czar et al. (2001) introduced a targeted mutation into the Sh2d1a gene of mice. Mice deficient in SLAM-associated protein had normal lymphocyte development, but on challenge with infectious agents, recapitulated features of XLP. Infection with lymphocytic choriomeningitis virus or Toxoplasma gondii was associated with increased T-cell activation and interferon-gamma production, as well as a reduction of immunoglobulin-secreting cells. Anti-CD3-stimulated splenocytes from uninfected mutant mice produced increased IFN-gamma and decreased IL4, findings supported by decreased serum IgE levels in vivo. The Th1 skewing of these animals suggested that cytokine misregulation may contribute to phenotypes associated with mutations of SH2D1A. </p><p>Using a Sap knockout mouse model, Crotty et al. (2003) found that Sap-deficient mice generated strong acute IgG antibody responses after lymphocytic choriomeningitis virus infection, but these titers rapidly waned and were accompanied by a paucity of long-lived plasma cells and memory B cells. Virus-specific memory CD4 (186940)-positive T cells were present in the Sap -/- mice. Histologic analysis demonstrated a severe reduction in the number and size of germinal centers. Using adoptive transfer and cell mixing experiments, Crotty et al. (2003) showed that the defect resided not in B cells but in the CD4-positive T cells of Sap-deficient mice. They concluded that SAP expression in CD4-positive T cells is essential for generating long-lived plasma cells and memory B cells. </p><p>Morra et al. (2005) found that mice lacking Sh2d1a had severely impaired primary and secondary responses of all Ig subclasses to specific antigens, even in the absence of viral infection. Fluorescence microscopy demonstrated that Sh2d1a was present in germinal centers in spleens of wildtype mice, but that germinal centers were absent in Sh2d1a-deficient mice after primary immunization. Adoptive transfer experiments showed that Sh2d1a expression was required in both B and T lymphocytes for responses to soluble T-dependent antigens. Morra et al. (2005) proposed that, in the absence of SH2D1A, progressive dysgammaglobulinemia can occur in XLP patients without the involvement of EBV. </p><p>Using 2-photon intravital imaging, Qi et al. (2008) showed that Sap deficiency in mice selectively impaired the ability of Cd4-positive T cells to interact with B lymphocytes, but not dendritic cells. This selective defect resulted in diminished levels of contact-dependent T-cell help, even though these T cells possessed other characteristics of competent helper T cells. Sap -/- T cells also displayed impaired recruitment to and retention in nascent germinal centers. Qi et al. (2008) concluded that the germinal center defect arising from Sap deficiency is caused by the inability of T cells to interact and communicate with cognate B cells, while interaction of T cells with dendritic cells remains unaffected. They proposed that SLAM family members may have a role in T- and B-cell interactions, and Deenick and Tangye (2008), in a commentary, suggested that the SLAM family member CD84 (604513) is a promising candidate. </p><p>Using a conditional gene targeting approach in mice and intracellular flow cytometric analysis, Veillette et al. (2008) showed that the defects in antibody production and memory B-cell generation in Sap-deficient mice, and presumably humans with XLP, resulted from lack of Sap expression in T cells, but not in B cells or NK cells. </p>
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</span>
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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>14 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 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</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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SH2D1A, ARG55TER
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<br />
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SNP: rs111033623,
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ClinVar: RCV000011645, RCV001091713, RCV001270156
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<span class="mim-text-font">
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<p>In a patient with X-linked lymphoproliferative disease (308240), Coffey et al. (1998) identified a 462C-T transition in the SH2D1A gene, resulting in an arg55-to-ter (R55X) substitution in the middle of the SH2 domain. </p><p>In 2 of 4 patients with XLP, Lappalainen et al. (2000) identified the R55X mutation. They noted that the mutation involves a CpG dinucleotide and suggested that nucleotide 462 is a mutation hotspot in the SH2D1A gene. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
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</span>
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<span class="mim-text-font">
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SH2D1A, GLN58TER
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<br />
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SNP: rs111033628,
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ClinVar: RCV000011646
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</span>
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<span class="mim-text-font">
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<p>In a patient with XLP (308240), Coffey et al. (1998) identified a 471C-T transition in the SH2D1A cDNA, resulting in a gln58-to-ter (Q58X) substitution. </p>
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</span>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</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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SH2D1A, 159-BP DEL
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<br />
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ClinVar: RCV000011647
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</span>
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</div>
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<span class="mim-text-font">
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<p>In 2 brothers with XLP (308240), Coffey et al. (1998) identified a 159-bp deletion following nucleotide 448 of the SH2D1A gene, which removed a 3-prime 53 bp of exon 2 and the 5-prime 106 bp of intronic sequence. This deletion removed 18 amino acids from the center of the SH2 domain, as well as the donor splice site at the end of the exon. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>.0004 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</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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SH2D1A, ARG32THR
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<br />
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SNP: rs111033624,
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|
|
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|
|
ClinVar: RCV000011648
|
|
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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 male with XLP (308240), Coffey et al. (1998) identified a 394G-C transversion in the SH2D1A gene, resulting in an arg32-to-thr (R32T) substitution. The presence of an arginine at position 32 in the SH2 domain is critical for phosphotyrosine binding. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
|
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</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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SH2D1A, IVS2AS, G-T, -1
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<br />
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|
SNP: rs1603238847,
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|
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ClinVar: RCV000011649
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
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<span class="mim-text-font">
|
|
<p>In 2 affected brothers with XLP (308240), Coffey et al. (1998) identified a 500G-T transversion in the SH2D1A gene. The change was in the last nucleotide of the exon, changing the splice site from AGgt to ATgt. RNA was not available; however, it was predicted that the mutation would inhibit correct splicing, as the mutation resulted in a reduction in the splice site score (Shapiro and Senapathy, 1987) from 81.8 (normal) to 69.0. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
|
|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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SH2D1A, TER129ARG
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<br />
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|
|
SNP: rs111033625,
|
|
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|
|
|
|
ClinVar: RCV000011650
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with XLP (308240), Coffey et al. (1998) identified a 684T-A transversion in the SH2D1A gene, changing the normal termination codon to an arginine (X129R), resulting in an addition of 12 amino acids to the C terminus of the protein. The authors suggested that the C-terminal extension disrupts the folding of the SH2 domain or interferes with the interaction between the SH2 domain and its phosphotyrosine target. Alternatively, this mutation may disrupt an as yet unknown function of the normal C-terminal tail of the protein. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
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|
|
|
SH2D1A, PRO101LEU
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|
|
|
<br />
|
|
|
|
SNP: rs111033626,
|
|
|
|
|
|
|
|
ClinVar: RCV000011651
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with XLP (308240), Coffey et al. (1998) identified a 601C-T transition in the SH2D1A gene, resulting in a pro101-to-leu (P101L) amino acid substitution. The mutation was also demonstrated in 2 obligate carriers in the kindred. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
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|
|
|
SH2D1A, THR68ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs111033627,
|
|
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|
|
|
|
|
ClinVar: RCV000011652
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with XLP (308240), Coffey et al. (1998) identified a 502C-T transition in the SH2D1A gene, resulting in a thr68-to-ile (T68I) amino acid substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SH2D1A, -10C-T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1603236465,
|
|
|
|
|
|
|
|
ClinVar: RCV000011653
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with XLP (308240), Coffey et al. (1998) identified a C-to-T transition of position -10 in the promoter region of the SH2D1A gene, changing a potential CCAAT box to CTAAT. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SH2D1A, EX1DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000011654
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 brothers with XLP (308240) who presented with B-cell non-Hodgkin lymphoma without evidence of Epstein-Barr virus infection, Brandau et al. (1999) and Strahm et al. (2000) identified a deletion in the first exon of the SH2D1A gene. The brothers presented at ages 4 and 2 years, respectively. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SH2D1A, MET1ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs111033629,
|
|
|
|
|
|
|
|
ClinVar: RCV000011655
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with multiple XLP (308240) deaths from fulminant hepatitis or leukemia after EBV infection, Parolini et al. (2000) identified a G-to-T transversion at nucleotide 3 in the translation initiation codon of the SH2D1A gene, resulting in a met1-to-ile substitution. The mutation was demonstrated in a healthy 3-year-old and in obligate carriers in the kindred. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SH2D1A, 163C-T
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000011645, RCV001091713, RCV001270156
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with XLP (308240) and in his 2 asymptomatic nephews, Parolini et al. (2000) identified a 163C-to-T transition in the SH2D1A gene, leading to a premature termination at codon 55. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SH2D1A, ARG55LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs111033630,
|
|
|
|
|
|
|
|
ClinVar: RCV000011657
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Benoit et al. (2000) identified an arg55-to-leu mutation in the second exon of the SH2D1A gene in autopsy specimens from 2 maternally related cousins diagnosed with XLP (308240). They also identified the mutation in 2 healthy, EBV-seronegative males in the extended family. Based on the molecular structure of the SH2D1A-SLAM (603492) interaction, this mutation was predicted to disrupt binding between the SH2 domain of SH2D1A and the cytoplasmic domain of SLAM. The mutation was also predicted to interfere with SH2D1A-2B4 (605554) binding because of the strong amino acid homology shared by SLAM and 2B4. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SH2D1A, IVS1DS, G-C, +5
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777612,
|
|
|
|
|
|
|
|
ClinVar: RCV000133459
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Recher et al. (2013) reported a 2-year-old Caucasian boy of nonconsanguineous parents who developed recurrent suppurative otitis media at 8 months of age followed by other bacterial and viral, but not EBV, infections. At 13 months of age, no serum IgG, IgA, or IgM was detectable, and B-cell levels were below normal. At 17 and 24 months of age, IgA and IgM remained undetectable, but B-cell numbers were within normal range. NKT cells were undetectable. At 3 years of age, EBV viremia was found as part of a pre-bone marrow transplant evaluation, but it remained clinically silent and resolved after B-cell depleting therapy. Sequencing of the SH2D1A gene revealed a G-C transversion at position +5 in intron 1. Patient SH2D1A mRNA was of normal length and sequence, but its expression was reduced 10-fold compared with a healthy control. Western blot analysis showed reduced expression of a normal-sized SH2D1A protein. Flow cytometric analysis demonstrated virtual abrogation of SH2D1A expression. Sequence analysis of the parental SH2D1A genes revealed the mother to be the carrier of the mutation, with wildtype sequence in the father. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Scher (1982)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Aoukaty, A., Tan, R.
|
|
<strong>Role for glycogen synthase kinase-3 in NK cell cytotoxicity and X-linked lymphoproliferative disease.</strong>
|
|
J. Immun. 174: 4551-4558, 2005.
|
|
|
|
|
|
[PubMed: 15814676]
|
|
|
|
|
|
[Full Text: https://doi.org/10.4049/jimmunol.174.8.4551]
|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Arico, M., Imashuku, S., Clementi, R., Hibi, S., Teramura, T., Danesino, C., Haber, D. A., Nichols, K. E.
|
|
<strong>Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene.</strong>
|
|
Blood 97: 1131-1133, 2001.
|
|
|
|
|
|
[PubMed: 11159547]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1182/blood.v97.4.1131]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Benoit, L., Wang, X., Pabst, H. F., Dutz, J., Tan, R.
|
|
<strong>Cutting edge: defective NK cell activation in X-linked lymphoproliferative disease.</strong>
|
|
J. Immun. 165: 3549-3553, 2000.
|
|
|
|
|
|
[PubMed: 11034354]
|
|
|
|
|
|
[Full Text: https://doi.org/10.4049/jimmunol.165.7.3549]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Brandau, O., Schuster, V., Weiss, M., Hellebrand, H., Fink, F. M., Kreczy, A., Friedrich, W., Strahm, B., Niemeyer, C., Belohradsky, B. H., Meindl, A.
|
|
<strong>Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP).</strong>
|
|
Hum. Molec. Genet. 8: 2407-2413, 1999.
|
|
|
|
|
|
[PubMed: 10556288]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/8.13.2407]
|
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|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Chan, B., Lanyi, A., Song, H. K., Griesbach, J., Simarro-Grande, M., Poy, F., Howie, D., Sumegi, J., Terhorst, C., Eck, M. J.
|
|
<strong>SAP couples Fyn to SLAM immune receptors.</strong>
|
|
Nature Cell Biol. 5: 155-160, 2003.
|
|
|
|
|
|
[PubMed: 12545174]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ncb920]
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Coffey, A. J., Brooksbank, R. A., Brandau, O., Oohashi, T., Howell, G. R., Bye, J. M., Cahn, A. P., Durham, J., Heath, P., Wray, P., Pavitt, R., Wilkinson, J., and 31 others.
|
|
<strong>Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.</strong>
|
|
Nature Genet. 20: 129-135, 1998.
|
|
|
|
|
|
[PubMed: 9771704]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/2424]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
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Wu, C., Nguyen, K. B., Pien, G. C., Wang, N., Gullo, C., Duncan, H., Sosa, M. R., Edwards, M. J., Borrow, P., Satoskar, A. R., Sharpe, A. H., Biron, C. A., Terhorst, C.
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<strong>SAP controls T cell responses to virus and terminal differentiation of T(H)2 cells.</strong>
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Nature Immun. 2: 410-414, 2001.
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[PubMed: 11323694]
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[Full Text: https://doi.org/10.1038/87713]
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Yin, L., Ferrand, V., Lavoue, M.-F., Hayoz, D., Philippe, N., Souillet, G., Seri, M., Giacchino, R., Castagnola, E., Hodgson, S., Sylla, B. S., Romeo, G.
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<strong>SH2D1A mutation analysis for diagnosis of XLP in typical and atypical patients.</strong>
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Hum. Genet. 105: 501-505, 1999.
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[PubMed: 10598819]
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[Full Text: https://doi.org/10.1007/s004390051137]
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Yin, L., Tocco, T., Pauly, S., Lenoir, G. M., Romeo, G.
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<strong>Absence of SH2D1A point mutation in 62 Burkitts lymphoma cell lines.</strong>
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Am. J. Hum. Genet. 65 (suppl. 1868): A331 only, 1999.
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