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Entry
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- *602839 - PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, DELTA; PIK3CD
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- OMIM
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<p>
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<span class="h4">*602839</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602839">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="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=ENSG00000171608;t=ENST00000377346" 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=5293" 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=602839" 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 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=ENSG00000171608;t=ENST00000377346" 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_001350234,NM_001350235,NM_005026,XM_006710687,XM_006710689,XM_024447663,XM_024447664,XM_047422550,XM_047422551,XM_047422552,XM_047422553,XM_047422554,XM_047422555,XM_047422556,XM_047422557,XM_047422558,XM_047422559,XM_047422560,XM_047422561,XM_047422562,XM_047422563,XM_047422564,XM_047422565,XM_047422566,XM_047422567,XM_047422568,XM_047422569,XM_047422570,XM_047422571,XM_047422572,XM_047422573,XM_047422574,XM_047422575,XM_047422576,XM_047422577,XM_047422578,XM_047422580,XM_047422589" 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_005026" 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=602839" 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=04161&isoform_id=04161_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/PIK3CD" 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/2076751,2317894,37496959,62087250,67477424,82570682,82570684,82570686,119592028,119592029,119592030,119592031,119592032,119592033,124376218,124376938,152012554,156564405,189054350,194382612,219519066,341580818,578799241,578799245,1137645639,1137645641,1137645643,1137645645,1176461144,1176461146,1370453477,1370453479,2217268151,2217268153,2217268155,2217268157,2217268159,2217268161,2217268163,2217268166,2217268168,2217268170,2217268172,2217268175,2217268177,2217268179,2217268181,2217268183,2217268186,2217268188,2217268190,2217268192,2217268194,2217268196,2217268198,2217268200,2217268202,2217268204,2217268206,2217268208,2217268210,2217268212,2217268214,2462510080,2462510082,2462510084,2462510086,2462510088,2462510090,2462510092,2462510094,2462510096,2462510098,2462510100,2462510102,2462510104,2462510106,2462510108,2462510110,2462510112,2462510114,2462510116,2462510118,2462510120,2462510122,2462510124,2462510126,2462510128,2462510130,2462510132,2462510134,2462510136,2462510138,2462510140,2462510142,2462510144,2462510146" 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/O00329" 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=5293" 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=ENSG00000171608;t=ENST00000377346" 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=PIK3CD" 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=PIK3CD" 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+5293" 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/PIK3CD" 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:5293" 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/5293" 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=chr1&hgg_gene=ENST00000377346.9&hgg_start=9627258&hgg_end=9729114&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/genes/HGNC:8977" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/pik3cd" 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=602839[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=602839[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/ENSG00000171608" 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=PIK3CD" 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=PIK3CD" 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=PIK3CD" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=PIK3CD&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/PA33310" 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:8977" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0015279.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1098211" 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/PIK3CD#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:1098211" 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/5293/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=5293" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00000090;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040426-1128" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
|
|
<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<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:5293" 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=PIK3CD&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> 711480000<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>
|
|
602839
|
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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>
|
|
<h3>
|
|
<span class="mim-font">
|
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PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, DELTA; PIK3CD
|
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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">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, 110-KD, DELTA<br />
|
|
p110-DELTA<br />
|
|
PI3K-DELTA<br />
|
|
PIK3-DELTA
|
|
</span>
|
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</h4>
|
|
</div>
|
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</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PIK3CD" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PIK3CD</a></em></strong>
|
|
</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/1/128?start=-3&limit=10&highlight=128">1p36.22</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:9627258-9729114&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'})">1:9,627,258-9,729,114</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=613328,615513,619281" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/128?start=-3&limit=10&highlight=128">
|
|
1p36.22
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
?Roifman-Chitayat syndrome, digenic
|
|
|
|
<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
|
</span>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
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PheneGene Graphics <span class="caret"></span>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3-prime OH position of the inositol ring of inositol lipids. PIK3CD is a class I PI3K and displays a broad phosphoinositide lipid substrate specificity (<a href="#17" class="mim-tip-reference" title="Vanhaesebroeck, B., Welham, M. J., Kotani, K., Stein, R., Warne, P. H., Zvelebil, M. J., Higashi, K., Volinia, S., Downward, J., Waterfield, M. D. <strong>p110-delta, a novel phosphoinositide 3-kinase in leukocytes.</strong> Proc. Nat. Acad. Sci. 94: 4330-4335, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9113989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9113989</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9113989[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.94.9.4330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9113989">Vanhaesebroeck et al., 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9113989" 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 RT-PCR of mRNA from a T-cell line with degenerate primers derived from conserved regions of PI3K catalytic core domains, <a href="#17" class="mim-tip-reference" title="Vanhaesebroeck, B., Welham, M. J., Kotani, K., Stein, R., Warne, P. H., Zvelebil, M. J., Higashi, K., Volinia, S., Downward, J., Waterfield, M. D. <strong>p110-delta, a novel phosphoinositide 3-kinase in leukocytes.</strong> Proc. Nat. Acad. Sci. 94: 4330-4335, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9113989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9113989</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9113989[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.94.9.4330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9113989">Vanhaesebroeck et al. (1997)</a> isolated a cDNA encoding a protein that they designated p110-delta. Sequence analysis revealed that the predicted 1,044-amino acid p110-delta protein is a PI3K that is 58% identical to p110-beta (<a href="/entry/602925">602925</a>). By Northern blot analysis of human tissues and immunolocalization in rat tissues, <a href="#17" class="mim-tip-reference" title="Vanhaesebroeck, B., Welham, M. J., Kotani, K., Stein, R., Warne, P. H., Zvelebil, M. J., Higashi, K., Volinia, S., Downward, J., Waterfield, M. D. <strong>p110-delta, a novel phosphoinositide 3-kinase in leukocytes.</strong> Proc. Nat. Acad. Sci. 94: 4330-4335, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9113989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9113989</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9113989[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.94.9.4330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9113989">Vanhaesebroeck et al. (1997)</a> found that p110-delta is selectively expressed in leukocytes. The p110-delta transcript is approximately 6 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9113989" 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="#14" class="mim-tip-reference" title="Seki, N., Nimura, Y., Ohira, M., Saito, T., Ichimiya, S., Nomura, N., Nakagawara, A. <strong>Identification and chromosome assignment of a human gene encoding a novel phosphatidylinositol-3 kinase.</strong> DNA Res. 4: 355-358, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9455486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9455486</a>] [<a href="https://doi.org/10.1093/dnares/4.5.355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9455486">Seki et al. (1997)</a> also cloned and characterized PIK3CD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9455486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Chantry, D., Vojtek, A., Kashishian, A., Holtzman, D. A., Wood, C., Gray, P. W., Cooper, J. A., Hoekstra, M. F. <strong>p110-delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes.</strong> J. Biol. Chem. 272: 19236-19241, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9235916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9235916</a>] [<a href="https://doi.org/10.1074/jbc.272.31.19236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9235916">Chantry et al. (1997)</a> isolated mouse and human p110-delta cDNAs. Sequence analysis revealed that the predicted proteins are 94% identical. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9235916" 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="Clayton, E., McAdam, S., Coadwell, J., Chantry, D., Turner, M. <strong>Structural organization of the mouse phosphatidylinositol 3-kinase p110d gene.</strong> Biochem. Biophys. Res. Commun. 280: 1328-1332, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11162674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11162674</a>] [<a href="https://doi.org/10.1006/bbrc.2001.4281" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11162674">Clayton et al. (2001)</a> determined that the mouse Pik3cd gene contains 22 exons and spans over 13 kb. Its exon structure most closely resembles that of Pik3cb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11162674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using FISH and radiation hybrid analysis, <a href="#14" class="mim-tip-reference" title="Seki, N., Nimura, Y., Ohira, M., Saito, T., Ichimiya, S., Nomura, N., Nakagawara, A. <strong>Identification and chromosome assignment of a human gene encoding a novel phosphatidylinositol-3 kinase.</strong> DNA Res. 4: 355-358, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9455486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9455486</a>] [<a href="https://doi.org/10.1093/dnares/4.5.355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9455486">Seki et al. (1997)</a> mapped the PIK3CD gene to chromosome 1p36.2, a region frequently lost in malignancy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9455486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Clayton, E., McAdam, S., Coadwell, J., Chantry, D., Turner, M. <strong>Structural organization of the mouse phosphatidylinositol 3-kinase p110d gene.</strong> Biochem. Biophys. Res. Commun. 280: 1328-1332, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11162674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11162674</a>] [<a href="https://doi.org/10.1006/bbrc.2001.4281" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11162674">Clayton et al. (2001)</a> suggested that the mouse Pik3d gene may be located on chromosome 4 in a region of syntenic homology with human chromosome 1p36.2-p32. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11162674" 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="#17" class="mim-tip-reference" title="Vanhaesebroeck, B., Welham, M. J., Kotani, K., Stein, R., Warne, P. H., Zvelebil, M. J., Higashi, K., Volinia, S., Downward, J., Waterfield, M. D. <strong>p110-delta, a novel phosphoinositide 3-kinase in leukocytes.</strong> Proc. Nat. Acad. Sci. 94: 4330-4335, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9113989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9113989</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9113989[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.94.9.4330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9113989">Vanhaesebroeck et al. (1997)</a> classified p110-delta as a class I PI3K because it displayed broad in vitro lipid substrate specificity. Like p110-alpha (PIK3CA; <a href="/entry/171834">171834</a>) and p110-beta, p110-delta binds p85 adaptor proteins and GTP-bound Ras. These 3 class I PI3Ks were indistinguishable at the level of p85 adaptor protein selection or recruitment to activated receptor complexes. However, unlike p110-alpha, p110-delta does not phosphorylate p85, but instead has an autophosphorylation activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9113989" 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="#18" class="mim-tip-reference" title="Zhang, J., Vanhaesebroeck, B., Rittenhouse, S. E. <strong>Human platelets contain p110-delta phosphoinositide 3-kinase.</strong> Biochem. Biophys. Res. Commun. 296: 178-181, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12147247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12147247</a>] [<a href="https://doi.org/10.1016/s0006-291x(02)00744-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12147247">Zhang et al. (2002)</a> noted that p110-delta had not detected in platelets. By examining human platelets, they found that p110-delta was highly susceptible to proteolytic degradation. Using Western blot, RT-PCR, activity, and immunoprecipitation analyses of lysed human platelets and detergent-insoluble cytoskeletal fractions from resting and thrombin receptor (F2R; <a href="/entry/187930">187930</a>)-activated human platelets, <a href="#18" class="mim-tip-reference" title="Zhang, J., Vanhaesebroeck, B., Rittenhouse, S. E. <strong>Human platelets contain p110-delta phosphoinositide 3-kinase.</strong> Biochem. Biophys. Res. Commun. 296: 178-181, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12147247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12147247</a>] [<a href="https://doi.org/10.1016/s0006-291x(02)00744-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12147247">Zhang et al. (2002)</a> showed that p110-delta was present in association with p85-alpha (PIK3R1; <a href="/entry/171833">171833</a>) and p85-beta (PIK3R2; <a href="/entry/603157">603157</a>) in both cytosolic and cytoskeletal fractions of platelets. <a href="#18" class="mim-tip-reference" title="Zhang, J., Vanhaesebroeck, B., Rittenhouse, S. E. <strong>Human platelets contain p110-delta phosphoinositide 3-kinase.</strong> Biochem. Biophys. Res. Commun. 296: 178-181, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12147247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12147247</a>] [<a href="https://doi.org/10.1016/s0006-291x(02)00744-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12147247">Zhang et al. (2002)</a> proposed that cytoskeletal function in activated platelets and platelet spawning from megakaryocytes may be influenced by p110-delta. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12147247" 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="Ali, K., Bilancio, A., Thomas, M., Pearce, W., Gilfillan, A. M., Tkaczyk, C., Kuehn, N., Gray, A., Giddings, J., Peskett, E., Fox, R., Bruce, I., Walker, C., Sawyer, C., Okkenhaug, K., Finan, P., Vanhaesebroeck, B. <strong>Essential role for the p110-delta phosphoinositide 3-kinase in the allergic response.</strong> Nature 431: 1007-1011, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15496927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15496927</a>] [<a href="https://doi.org/10.1038/nature02991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15496927">Ali et al. (2004)</a> reported that genetic or pharmacologic inactivation of the p110-delta isoform of PI(3)K in mast cells led to defective stem cell factor (SCF; <a href="/entry/184745">184745</a>)-mediated in vitro proliferation, adhesion, and migration, and to impaired allergen-IgE (<a href="/entry/147180">147180</a>)-induced degranulation and cytokine release. Inactivation of p110-delta protected mice against anaphylactic allergic responses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15496927" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Ali, K., Soond, D. R., Pineiro, R., Hagemann, T., Pearce, W., Lim, E. L., Bouabe, H., Scudamore, C. L., Hancox, T., Maecker, H., Friedman, L., Turner, M., Okkenhaug, K., Vanhaesebroeck, B. <strong>Inactivation of PI(3)K p110-delta breaks regulatory T-cell-mediated immune tolerance to cancer.</strong> Nature 510: 407-411, 2014. Note: Erratum: Nature 535: 580 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24919154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24919154</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24919154[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/nature13444" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24919154">Ali et al. (2014)</a> reported that p110-delta inactivation in mice protects against a broad range of cancers, including nonhematologic solid tumors, and demonstrated that p110-delta inactivation in regulatory T cells unleashes CD8+ cytotoxic T cells and induces tumor regression. <a href="#2" class="mim-tip-reference" title="Ali, K., Soond, D. R., Pineiro, R., Hagemann, T., Pearce, W., Lim, E. L., Bouabe, H., Scudamore, C. L., Hancox, T., Maecker, H., Friedman, L., Turner, M., Okkenhaug, K., Vanhaesebroeck, B. <strong>Inactivation of PI(3)K p110-delta breaks regulatory T-cell-mediated immune tolerance to cancer.</strong> Nature 510: 407-411, 2014. Note: Erratum: Nature 535: 580 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24919154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24919154</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24919154[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/nature13444" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24919154">Ali et al. (2014)</a> concluded that p110-delta inhibitors can break tumor-induced immune tolerance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24919154" 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><strong><em>Autosomal Dominant Immunodeficiency 14A With Lymphoproliferation</em></strong></p><p>
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In 17 patients from 7 unrelated families with autosomal dominant primary immunodeficiency-14A (IMD14A; <a href="/entry/615513">615513</a>), <a href="#3" class="mim-tip-reference" title="Angulo, I., Vadas, O., Garcon, F., Banham-Hall, E., Plagnol, V., Leahy, T. R., Baxendale, H., Coulter, T., Curtis, J., Wu, C., Blake-Palmer, K., Perisic, O., and 32 others. <strong>Phosphoinositide 3-kinase-delta gene mutation predisposes to respiratory infection and airway damage.</strong> Science 342: 866-871, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24136356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24136356</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24136356[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1243292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24136356">Angulo et al. (2013)</a> identified the same heterozygous missense mutation (<a href="#0001">602839.0001</a>) in the PIK3CD gene that resulted in a dominant gain of function. The E1021K mutation enhanced membrane association and kinase activity of p110-delta. Selective p110-delta inhibitors reduced the activity of the mutant enzyme in vitro, suggesting a therapeutic approach for these patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24136356" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Taiwanese boy of Chinese descent with IMD14A, <a href="#9" class="mim-tip-reference" title="Jou, S.-T., Chien, Y.-H., Yang, Y.-H., Wang, T.-C., Shyur, S.-D., Chou, C.-C., Chang, M.-L., Lin, D.-T., Lin, K.-H., Chiang, B.-L. <strong>Identification of variations in the human phosphoinositide 3-kinase p110-delta gene in children with primary B-cell immunodeficiency of unknown aetiology.</strong> Int. J. Immunogenet. 33: 361-369, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16984281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16984281</a>] [<a href="https://doi.org/10.1111/j.1744-313X.2006.00627.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16984281">Jou et al. (2006)</a> identified a heterozygous missense mutation in the PIK3CD gene (E1021K; <a href="#0001">602839.0001</a>). Functional studies of the variant were not performed. The PIK3CD gene was chosen for study because Pik3cd-null mice show a B-cell immunodeficiency; the patient was the only one of 15 probands with immunodeficiency who was found to carry a pathogenic PIK3CD mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16984281" 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 14 patients from 7 unrelated families with IMD14A, <a href="#10" class="mim-tip-reference" title="Lucas, C. L., Kuehn, H. S., Zhao, F., Niemela, J. E., Deenick, E. K., Palendira, U., Avery, D. T., Moens, L., Cannons, J. L., Biancalana, M., Stoddard, J., Ouyang, W., and 16 others. <strong>Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110-delta result in T cell senescence and human immunodeficiency.</strong> Nature Immun. 15: 88-97, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24165795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24165795</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24165795[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/ni.2771" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24165795">Lucas et al. (2014)</a> identified 3 different heterozygous gain-of-function mutations in the PIK3CD gene (<a href="#0001">602839.0001</a>-<a href="#0003">602839.0003</a>). The mutations were found by whole-exome sequencing and targeted Sanger sequencing. Studies of patient-derived cells and control cells showed that the mutations caused increased phosphorylation of AKT (<a href="/entry/164730">164730</a>) compared to wildtype PIK3CD, consistent with a gain of function. Patient CD8+ T cells had an effector memory phenotype and were more activated compared to controls, suggesting that a large proportion of these cells are in a terminally differentiated state with a corresponding low proliferative capacity. Patient T cells showed hyperphosphorylation of the downstream mTOR (<a href="/entry/601231">601231</a>) signaling pathway, which resulted in increased glucose usage in the cells and predisposition to differentiation and senescence. Treatment of 1 patient with rapamycin, which inhibits mTOR, resulted in a reduction in CD8+ T cells to normal numbers and an increase in naive T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24165795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 patients from 2 unrelated families with IMD14A manifest as hyper-IgM and B-cell lymphoma, <a href="#8" class="mim-tip-reference" title="Crank, M. C., Grossman, J. K., Moir, S., Pittaluga, S., Buckner, C. M., Kardava, L., Agharahimi, A., Meuwissen, H., Stoddard, J., Niemela, J., Kuehn, H., Rosenzweig, S. D. <strong>Mutations in PIK3CD can cause hyper IgM syndrome associated with increased cancer susceptibility.</strong> J. Clin. Immun. 34: 272-276, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24610295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24610295</a>] [<a href="https://doi.org/10.1007/s10875-014-0012-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24610295">Crank et al. (2014)</a> identified 2 heterozygous gain-of-function mutations in the PIK3CD gene (<a href="#0001">602839.0001</a> and <a href="#0004">602839.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24610295" 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="#4" class="mim-tip-reference" title="Avery, D. T., Kane, A., Nguyen, T., Lau, A., Nguyen, A., Lenthall, H., Payne, K., Shi, W., Brigden, H., French, E., Bier, J., Hermes, J. R., and 22 others. <strong>Germline-activating mutations in PIK3CD compromise B cell development and function.</strong> J. Exp. Med. 215: 2073-2095, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30018075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30018075</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30018075[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.20180010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30018075">Avery et al. (2018)</a> studied a large cohort of patients with PIK3CD gain-of-function mutations and established a mouse model with a heterozygous activating Pik3cd mutation (E1020K, which is orthologous to the human E1021K mutation). In both species, hyperactivation of PI3K-dependent signaling pathways led to decreased mature B cells in bone marrow and in the periphery. Further analysis showed impaired Ig class switching, but no effect on proliferation and affinity maturation of B cells. Intrinsic defects in Ig class-switch recombination (CSR) in B-cell differentiation were caused by reduction in activation-induced cytidine deaminase (AID; <a href="/entry/605257">605257</a>) expression in B cells and by failure to acquire a plasmablast gene signature and phenotype. These defects in B-cell differentiation could be partially overcome by treatment with a specific PIK3CD inhibitor, which restored CSR, AID expression, and Ig secretion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30018075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Roifman-Chitayat Syndrome</em></strong></p><p>
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In 2 sibs, born of consanguineous parents, with Roifman-Chitayat syndrome (ROCHIS; <a href="/entry/613328">613328</a>) originally reported by <a href="#13" class="mim-tip-reference" title="Roifman, C. M., Chitayat, D. <strong>Combined immunodeficiency, facial dysmorphism, optic nerve atrophy, skeletal anomalies and developmental delay: a new syndrome.</strong> Clin. Genet. 76: 449-457, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19863561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19863561</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01239.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19863561">Roifman and Chitayat (2009)</a>, <a href="#15" class="mim-tip-reference" title="Sharfe, N., Karanxha, A., Dadi, H., Merico, D., Chitayat, D., Herbrick, J.-A., Freeman, S., Grinstein, S., Roifman, C. M. <strong>Dual loss of p110-delta PI3-kinase and SKAP (KNSTRN) expression leads to combined immunodeficiency and multisystem syndromic features.</strong> J. Allergy Clin. Immun. 142: 618-629, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29180244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29180244</a>] [<a href="https://doi.org/10.1016/j.jaci.2017.10.033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29180244">Sharfe et al. (2018)</a> identified homozygous loss-of-function mutations in 2 different genes: PIK3CD (<a href="#0005">602839.0005</a>) and SKAP (KNSTRN; <a href="/entry/614718#0001">614718.0001</a>). The mutations, which were found by whole-genome sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed no detectable PIK3CD or KNSTRN proteins, consistent with a loss of function of both genes. Patient cells showed a near absence of AKT (<a href="/entry/164730">164730</a>) phosphorylation compared to controls, revealing defective PIK3CD function. Detailed in vitro studies showed that patient-derived B and T lymphocytes failed to cluster or aggregate properly, similar to abnormalities noted in SKAP-null cells, suggesting that SKAP deficiency was responsible for this feature. In addition, T cells showed reduced spontaneous migration and inefficient cell-cell contact formation due to limited cell spreading. These abnormalities were associated with aberrant MAP4 (<a href="/entry/157132">157132</a>) distribution and localized altered microtubule acetylation, which was attributed to loss of SKAP. <a href="#15" class="mim-tip-reference" title="Sharfe, N., Karanxha, A., Dadi, H., Merico, D., Chitayat, D., Herbrick, J.-A., Freeman, S., Grinstein, S., Roifman, C. M. <strong>Dual loss of p110-delta PI3-kinase and SKAP (KNSTRN) expression leads to combined immunodeficiency and multisystem syndromic features.</strong> J. Allergy Clin. Immun. 142: 618-629, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29180244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29180244</a>] [<a href="https://doi.org/10.1016/j.jaci.2017.10.033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29180244">Sharfe et al. (2018)</a> concluded that the complex phenotype resulted from the concurrent loss of 2 different genes, each of which contributed to the disease manifestations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=29180244+19863561" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Autosomal Recessive Immunodeficiency 14B</em></strong></p><p>
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In 2 brothers, born of consanguineous Pakistani parents, with autosomal recessive immunodeficiency-14B (IMD14B; <a href="/entry/619281">619281</a>), <a href="#16" class="mim-tip-reference" title="Sogkas, G., Fedchenko, M., Dhingra, A., Jablonka, A., Schmidt, R. E., Atschekzei, F. <strong>Primary immunodeficiency disorder caused by phosphoinositide 3-kinase delta deficiency.</strong> J. Allergy Clin. Immun. 142: 1650-1653.e2, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30040974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30040974</a>] [<a href="https://doi.org/10.1016/j.jaci.2018.06.039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30040974">Sogkas et al. (2018)</a> identified a homozygous frameshift mutation in the PIK3CD gene (<a href="#0006">602839.0006</a>). The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient T cells showed impaired AKT phosphorylation after stimulation with an anti-CD3 antibody, suggesting a loss of PIK3CD function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30040974" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a boy, born of consanguineous Pakistani parents, with IMD14B, <a href="#7" class="mim-tip-reference" title="Cohen, S. B., Bainter, W., Johnson, J. L., Lin, T.-Y., Wong, J. C. Y., Wallace, J. G., Jones, J., Qureshi, S., Mir, F., Qamar, F., Cantley, L. C., Geha, R. S., Chou, J. <strong>Human primary immunodeficiency caused by expression of a kinase-dead p110-delta mutant.</strong> J. Allergy Clin. Immun. 143: 797-799.e2, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30336224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30336224</a>] [<a href="https://doi.org/10.1016/j.jaci.2018.10.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30336224">Cohen et al. (2019)</a> identified a homozygous frameshift mutation in the PIK3CD gene (<a href="#0007">602839.0007</a>). The mutation, which was found by whole-exome sequencing, was predicted to disrupt the ATP binding site in the catalytic domain. The mutation was not found in the 1000 Genomes Project, ExAC, or Exome Sequencing Project databases. In vitro functional expression studies in HEK293T cells transfected with the mutation showed that the truncated protein was expressed, but lacked kinase activity, consistent with a loss of function. Patient T cells showed decreased calcium flux after CD3 stimulation compared to controls, suggesting impaired cellular immunity. Noting that dominant gain-of-function mutations in the PIK3CD gene can cause IMD14A, both <a href="#16" class="mim-tip-reference" title="Sogkas, G., Fedchenko, M., Dhingra, A., Jablonka, A., Schmidt, R. E., Atschekzei, F. <strong>Primary immunodeficiency disorder caused by phosphoinositide 3-kinase delta deficiency.</strong> J. Allergy Clin. Immun. 142: 1650-1653.e2, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30040974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30040974</a>] [<a href="https://doi.org/10.1016/j.jaci.2018.06.039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30040974">Sogkas et al. (2018)</a> and <a href="#7" class="mim-tip-reference" title="Cohen, S. B., Bainter, W., Johnson, J. L., Lin, T.-Y., Wong, J. C. Y., Wallace, J. G., Jones, J., Qureshi, S., Mir, F., Qamar, F., Cantley, L. C., Geha, R. S., Chou, J. <strong>Human primary immunodeficiency caused by expression of a kinase-dead p110-delta mutant.</strong> J. Allergy Clin. Immun. 143: 797-799.e2, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30336224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30336224</a>] [<a href="https://doi.org/10.1016/j.jaci.2018.10.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30336224">Cohen et al. (2019)</a> concluded that precise regulation of PIK3CD activity is required for proper immune function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30336224+30040974" 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="Rodriguez, R., Fournier, B., Cordeiro, D. J., Winter, S., Izawa, K., Martin, E., Boutboul, D., Lenoir, C., Fraitag, S., Kracker, S., Watts, T. H., Picard, C., Bruneau, J., Callebaut, I., Fischer, A., Neven, B., Latour, S. <strong>Concomitant PIK3CD and TNFRSF9 deficiencies cause chronic active Epstein-Barr virus infection of T cells.</strong> J. Exp. Med. 216: 2800-2818, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31537641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31537641</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31537641[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.20190678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31537641">Rodriguez et al. (2019)</a> reported a 14-year-old boy, born of consanguineous Pakistani parents, with recurrent infections beginning in infancy who later developed chronic T-cell EBV infection with high EBV loads associated with hepatosplenomegaly and lymphadenopathies. At 14 years of age, he developed an acute episode of hemophagocytic lymphohistiocytosis (HLH) and died of the disease. His 6-year-old sister had an elevated blood EBV load in the absence of clinical symptoms. Whole-exome sequencing of the proband identified a homozygous frameshift variant (c.170delG) in the TNFRSF9 (CD137) gene (<a href="/entry/602250">602250</a>) that was also present in the homozygous state in his sister and in the heterozygous state in other unaffected family members. Studies of patient T cells showed lack of CD137 expression, suggesting that the variant results in a loss-of-function effect. Further studies identified a homozygous missense variant (R821H) in the PIK3CD gene that was present only in the proband; it was heterozygous in other family members, including the asymptomatic sister. The R821H variant was associated with reduced but residual kinase activity, consistent with a functional deficit. The authors suggested that CD137 deficiency likely accounts for the impaired immune control of EBV-infected T cells, whereas the mutation in the PIK3CD gene may act as a driver mutation allowing EBV-infected T cells to persist and proliferate uncontrollably. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31537641" 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="Okkenhaug, K., Bilancio, A., Farjot, G., Priddle, H., Sancho, S., Peskett, E., Pearce, W., Meek, S. E., Salpekar, A., Waterfield, M. D., Smith, A. J. H., Vanhaesebroeck, B. <strong>Impaired B and T cell antigen receptor signaling in p110-delta PI 3-kinase mutant mice.</strong> Science 297: 1031-1034, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12130661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12130661</a>] [<a href="https://doi.org/10.1126/science.1073560" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12130661">Okkenhaug et al. (2002)</a> generated mice expressing a catalytically inactive form of Pik3cd (asp910 to ala). They observed impaired signaling and attenuated immune responses by antigen receptors of B and T cells from these mice. The presence of Pik3ca and Pik3cb did not compensate for Pik3cd in immune function. The mutant mice also developed inflammatory bowel disease. Since the IBD7 susceptibility locus (<a href="/entry/605225">605225</a>) maps to chromosome 1p36, the authors suggested that PIK3CD may be a candidate susceptibility gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12130661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a Taiwanese boy of Chinese descent with primary immunodeficiency-14A (IMD14A; <a href="/entry/615513">615513</a>), <a href="#9" class="mim-tip-reference" title="Jou, S.-T., Chien, Y.-H., Yang, Y.-H., Wang, T.-C., Shyur, S.-D., Chou, C.-C., Chang, M.-L., Lin, D.-T., Lin, K.-H., Chiang, B.-L. <strong>Identification of variations in the human phosphoinositide 3-kinase p110-delta gene in children with primary B-cell immunodeficiency of unknown aetiology.</strong> Int. J. Immunogenet. 33: 361-369, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16984281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16984281</a>] [<a href="https://doi.org/10.1111/j.1744-313X.2006.00627.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16984281">Jou et al. (2006)</a> identified a heterozygous G-to-A transition in exon 24 of the PIK3CD gene, resulting in a glu1021-to-lys (E1021K) substitution at a highly conserved residue in the catalytic domain. The mutation was not found in his parents or in 112 control individuals. Functional studies of the variant were not performed. The patient had had a primary B-cell deficiency with hypogammaglobulinemia and recurrent sinopulmonary infections since 7 months of age. The PIK3CD gene was chosen for study because Pik3cd-null mice show a B-cell immunodeficiency; the patient was the only one of 15 probands with immunodeficiency who was found to carry a pathogenic PIK3CD mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16984281" 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 17 individuals from 7 unrelated families with IMD14A, <a href="#3" class="mim-tip-reference" title="Angulo, I., Vadas, O., Garcon, F., Banham-Hall, E., Plagnol, V., Leahy, T. R., Baxendale, H., Coulter, T., Curtis, J., Wu, C., Blake-Palmer, K., Perisic, O., and 32 others. <strong>Phosphoinositide 3-kinase-delta gene mutation predisposes to respiratory infection and airway damage.</strong> Science 342: 866-871, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24136356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24136356</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24136356[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1243292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24136356">Angulo et al. (2013)</a> identified a heterozygous G-to-A transition at nucleotide 3061 of the PIK3CD gene that resulted in a glutamic acid-to-lysine substitution at codon 1021 (E1021K) of the p110-delta protein. All affected individuals carried this mutation. This mutation was not identified among 3,346 healthy subjects. In 1 affected individual the mutation occurred as a de novo event; otherwise inheritance was autosomal dominant. The E1021K mutation in the catalytic subunit results in gain of function causing enhanced membrane association and kinase activity. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT (<a href="/entry/164730">164730</a>) protein and were prone to activation-induced cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24136356" 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 6 patients from 3 families with IMD14A, <a href="#10" class="mim-tip-reference" title="Lucas, C. L., Kuehn, H. S., Zhao, F., Niemela, J. E., Deenick, E. K., Palendira, U., Avery, D. T., Moens, L., Cannons, J. L., Biancalana, M., Stoddard, J., Ouyang, W., and 16 others. <strong>Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110-delta result in T cell senescence and human immunodeficiency.</strong> Nature Immun. 15: 88-97, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24165795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24165795</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24165795[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/ni.2771" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24165795">Lucas et al. (2014)</a> identified a heterozygous E1021K mutation in the C-lobe of the kinase domain. The mutation was found by whole-exome sequencing and targeted Sanger sequencing. Structural analysis suggested that the E1021K substitution may enhance the recruitment of the protein to the plasma membrane and increase catalytic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24165795" 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="Crank, M. C., Grossman, J. K., Moir, S., Pittaluga, S., Buckner, C. M., Kardava, L., Agharahimi, A., Meuwissen, H., Stoddard, J., Niemela, J., Kuehn, H., Rosenzweig, S. D. <strong>Mutations in PIK3CD can cause hyper IgM syndrome associated with increased cancer susceptibility.</strong> J. Clin. Immun. 34: 272-276, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24610295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24610295</a>] [<a href="https://doi.org/10.1007/s10875-014-0012-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24610295">Crank et al. (2014)</a> identified an E1021K mutation in a 21-year-old Caucasian woman with IMD14A who had increased serum IgM and developed a large B-cell lymphoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24610295" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 12-year-old girl with autosomal dominant immunodeficiency-14A (IMD14A; <a href="/entry/615513">615513</a>), <a href="#10" class="mim-tip-reference" title="Lucas, C. L., Kuehn, H. S., Zhao, F., Niemela, J. E., Deenick, E. K., Palendira, U., Avery, D. T., Moens, L., Cannons, J. L., Biancalana, M., Stoddard, J., Ouyang, W., and 16 others. <strong>Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110-delta result in T cell senescence and human immunodeficiency.</strong> Nature Immun. 15: 88-97, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24165795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24165795</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24165795[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/ni.2771" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24165795">Lucas et al. (2014)</a> identified a heterozygous c.1002C-A transversion in the PIK3CD gene, resulting in an asn334-to-lys (N334K) substitution in the C2 domain. The mutation was found by whole-exome sequencing and targeted Sanger sequencing. Structural analysis suggested that the N334K substitution may disrupt inhibitory contacts between PIK3CD and the regulatory subunit (PIK3R1; <a href="/entry/171833">171833</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24165795" 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 IMMUNODEFICIENCY 14A WITH LYMPHOPROLIFERATION, AUTOSOMAL DOMINANT</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">rs587777389 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777389;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=rs587777389" 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=rs587777389" 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=RCV000119276 OR RCV004745195" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000119276, RCV004745195" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000119276...</a>
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<p>In 7 patients from 3 families with autosomal dominant immunodeficiency-14A (IMD14A; <a href="/entry/615513">615513</a>), <a href="#10" class="mim-tip-reference" title="Lucas, C. L., Kuehn, H. S., Zhao, F., Niemela, J. E., Deenick, E. K., Palendira, U., Avery, D. T., Moens, L., Cannons, J. L., Biancalana, M., Stoddard, J., Ouyang, W., and 16 others. <strong>Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110-delta result in T cell senescence and human immunodeficiency.</strong> Nature Immun. 15: 88-97, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24165795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24165795</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24165795[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/ni.2771" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24165795">Lucas et al. (2014)</a> identified a heterozygous c.1573G-A transition in the PIK3CD gene, resulting in a glu525-to-lys (E525K) substitution in the helical domain. The mutation was found by whole-exome sequencing and targeted Sanger sequencing. Structural analysis suggested that the N334K substitution may disrupt inhibitory contacts between PIK3CD and the regulatory subunit (PIK3R1; <a href="/entry/171833">171833</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24165795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 IMMUNODEFICIENCY 14A WITH LYMPHOPROLIFERATION, AUTOSOMAL DOMINANT</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">rs587777390 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777390;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=rs587777390" 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=rs587777390" 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=RCV000119277" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000119277" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000119277</a>
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<p>In 2 affected members of a family with autosomal dominant immunodeficiency-14A (IMD14A; <a href="/entry/615513">615513</a>), <a href="#8" class="mim-tip-reference" title="Crank, M. C., Grossman, J. K., Moir, S., Pittaluga, S., Buckner, C. M., Kardava, L., Agharahimi, A., Meuwissen, H., Stoddard, J., Niemela, J., Kuehn, H., Rosenzweig, S. D. <strong>Mutations in PIK3CD can cause hyper IgM syndrome associated with increased cancer susceptibility.</strong> J. Clin. Immun. 34: 272-276, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24610295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24610295</a>] [<a href="https://doi.org/10.1007/s10875-014-0012-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24610295">Crank et al. (2014)</a> identified a heterozygous c.1246T-C transition in the PIK3CD gene, resulting in a cys416-to-arg (C416R) substitution. The mutation was demonstrated to result in a gain of function with hyperphosphorylation of AKT (<a href="/entry/164730">164730</a>). Both patients had recurrent infections, lymphadenopathy, and increased serum IgM, and both developed B-cell lymphoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24610295" 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">rs2100976217 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2100976217;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=rs2100976217" 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=rs2100976217" 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=RCV002246350" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002246350" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002246350</a>
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<p>In 2 sisters, born of consanguineous parents, with Roifman-Chitayat syndrome (ROCHIS; <a href="/entry/613328">613328</a>) originally reported by <a href="#13" class="mim-tip-reference" title="Roifman, C. M., Chitayat, D. <strong>Combined immunodeficiency, facial dysmorphism, optic nerve atrophy, skeletal anomalies and developmental delay: a new syndrome.</strong> Clin. Genet. 76: 449-457, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19863561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19863561</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01239.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19863561">Roifman and Chitayat (2009)</a>, <a href="#15" class="mim-tip-reference" title="Sharfe, N., Karanxha, A., Dadi, H., Merico, D., Chitayat, D., Herbrick, J.-A., Freeman, S., Grinstein, S., Roifman, C. M. <strong>Dual loss of p110-delta PI3-kinase and SKAP (KNSTRN) expression leads to combined immunodeficiency and multisystem syndromic features.</strong> J. Allergy Clin. Immun. 142: 618-629, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29180244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29180244</a>] [<a href="https://doi.org/10.1016/j.jaci.2017.10.033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29180244">Sharfe et al. (2018)</a> identified a homozygous c.2161C-T transition in the PIK3CD gene, resulting in a gln721-to-ter (Q721X) substitution at the beginning of the kinase domain. The mutation, which was found by whole-genome sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed absence of the full-length protein, and near absence of AKT (<a href="/entry/164730">164730</a>) phosphorylation compared to controls, consistent with a loss of function. The patients were also homozygous for a loss-of-function mutation in the KNSTRN gene (<a href="/entry/614718#0001">614718.0001</a>). Loss of both genes contributed to the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=29180244+19863561" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 IMMUNODEFICIENCY 14B, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2100956273 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2100956273;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=rs2100956273" 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=rs2100956273" 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=RCV001374740" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001374740" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001374740</a>
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<p>In 2 brothers, born of consanguineous Pakistani parents, with autosomal recessive immunodeficiency-14B (IMD14B; <a href="/entry/619281">619281</a>), <a href="#16" class="mim-tip-reference" title="Sogkas, G., Fedchenko, M., Dhingra, A., Jablonka, A., Schmidt, R. E., Atschekzei, F. <strong>Primary immunodeficiency disorder caused by phosphoinositide 3-kinase delta deficiency.</strong> J. Allergy Clin. Immun. 142: 1650-1653.e2, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30040974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30040974</a>] [<a href="https://doi.org/10.1016/j.jaci.2018.06.039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30040974">Sogkas et al. (2018)</a> identified a homozygous 1-bp deletion (c.1653delG) in the PIK3CD gene, resulting in a frameshift and premature termination (Val552SerfsTer26). The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient T cells showed impaired AKT phosphorylation after stimulation with an anti-CD3 antibody, suggesting a loss of PIK3CD function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30040974" 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">rs2100990445 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2100990445;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=rs2100990445" 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=rs2100990445" 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=RCV001374741" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001374741" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001374741</a>
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<p>In a boy, born of consanguineous Pakistani parents, with autosomal recessive immunodeficiency-14B (IMD14B; <a href="/entry/619281">619281</a>), <a href="#7" class="mim-tip-reference" title="Cohen, S. B., Bainter, W., Johnson, J. L., Lin, T.-Y., Wong, J. C. Y., Wallace, J. G., Jones, J., Qureshi, S., Mir, F., Qamar, F., Cantley, L. C., Geha, R. S., Chou, J. <strong>Human primary immunodeficiency caused by expression of a kinase-dead p110-delta mutant.</strong> J. Allergy Clin. Immun. 143: 797-799.e2, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30336224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30336224</a>] [<a href="https://doi.org/10.1016/j.jaci.2018.10.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30336224">Cohen et al. (2019)</a> identified a homozygous 2-bp deletion (c.2558_2559delAT) in the PIK3CD gene, resulting in a frameshift and premature termination (Asp853GlyfsTer20). The mutation, which was found by whole-exome sequencing, was predicted to disrupt exons 20 to 24 encoding 171 residues of the ATP binding site in the catalytic domain. The mutation was not found in the 1000 Genomes Project, ExAC, or Exome Sequencing Project databases. In vitro functional expression studies in HEK293T cells transfected with the mutation showed that the truncated protein was expressed, but lacked kinase activity, consistent with a loss of function. Patient T cells showed decreased calcium flux after CD3 stimulation compared to controls, suggesting impaired cellular immunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30336224" 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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Cohen, S. B., Bainter, W., Johnson, J. L., Lin, T.-Y., Wong, J. C. Y., Wallace, J. G., Jones, J., Qureshi, S., Mir, F., Qamar, F., Cantley, L. C., Geha, R. S., Chou, J.
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<strong>Human primary immunodeficiency caused by expression of a kinase-dead p110-delta mutant.</strong>
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J. Allergy Clin. Immun. 143: 797-799.e2, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30336224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30336224</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30336224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jaci.2018.10.005" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1744-313X.2006.00627.x" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24165795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24165795</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24165795[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=24165795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12130661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12130661</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12130661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1073560" target="_blank">Full Text</a>]
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Rodriguez, R., Fournier, B., Cordeiro, D. J., Winter, S., Izawa, K., Martin, E., Boutboul, D., Lenoir, C., Fraitag, S., Kracker, S., Watts, T. H., Picard, C., Bruneau, J., Callebaut, I., Fischer, A., Neven, B., Latour, S.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31537641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31537641</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31537641[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=31537641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1084/jem.20190678" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19863561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19863561</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19863561" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2009.01239.x" target="_blank">Full Text</a>]
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Seki, N., Nimura, Y., Ohira, M., Saito, T., Ichimiya, S., Nomura, N., Nakagawara, A.
|
|
<strong>Identification and chromosome assignment of a human gene encoding a novel phosphatidylinositol-3 kinase.</strong>
|
|
DNA Res. 4: 355-358, 1997.
|
|
|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9455486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9455486</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9455486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/dnares/4.5.355" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Sharfe2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sharfe, N., Karanxha, A., Dadi, H., Merico, D., Chitayat, D., Herbrick, J.-A., Freeman, S., Grinstein, S., Roifman, C. M.
|
|
<strong>Dual loss of p110-delta PI3-kinase and SKAP (KNSTRN) expression leads to combined immunodeficiency and multisystem syndromic features.</strong>
|
|
J. Allergy Clin. Immun. 142: 618-629, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29180244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29180244</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29180244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jaci.2017.10.033" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Sogkas2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sogkas, G., Fedchenko, M., Dhingra, A., Jablonka, A., Schmidt, R. E., Atschekzei, F.
|
|
<strong>Primary immunodeficiency disorder caused by phosphoinositide 3-kinase delta deficiency.</strong>
|
|
J. Allergy Clin. Immun. 142: 1650-1653.e2, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30040974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30040974</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30040974" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jaci.2018.06.039" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Vanhaesebroeck1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vanhaesebroeck, B., Welham, M. J., Kotani, K., Stein, R., Warne, P. H., Zvelebil, M. J., Higashi, K., Volinia, S., Downward, J., Waterfield, M. D.
|
|
<strong>p110-delta, a novel phosphoinositide 3-kinase in leukocytes.</strong>
|
|
Proc. Nat. Acad. Sci. 94: 4330-4335, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9113989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9113989</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9113989[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=9113989" 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.94.9.4330" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Zhang2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, J., Vanhaesebroeck, B., Rittenhouse, S. E.
|
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<strong>Human platelets contain p110-delta phosphoinositide 3-kinase.</strong>
|
|
Biochem. Biophys. Res. Commun. 296: 178-181, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12147247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12147247</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12147247" 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/s0006-291x(02)00744-1" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 03/15/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 04/19/2021<br>Bao Lige - updated : 08/13/2018<br>Ada Hamosh - updated : 07/16/2014<br>Cassandra L. Kniffin - updated : 5/21/2014<br>Paul J. Converse - updated : 5/20/2014<br>Carol A. Bocchini - updated : 5/7/2014<br>Ada Hamosh - updated : 12/17/2013<br>Ada Hamosh - updated : 1/26/2005<br>Paul J. Converse - updated : 9/4/2002
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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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Rebekah S. Rasooly : 7/13/1998
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 03/16/2023
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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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alopez : 03/15/2023<br>ckniffin : 03/15/2023<br>carol : 04/22/2021<br>alopez : 04/21/2021<br>ckniffin : 04/19/2021<br>mgross : 08/13/2018<br>alopez : 08/02/2016<br>alopez : 07/16/2014<br>alopez : 5/23/2014<br>alopez : 5/23/2014<br>mcolton : 5/21/2014<br>ckniffin : 5/21/2014<br>mgross : 5/20/2014<br>mcolton : 5/15/2014<br>carol : 5/7/2014<br>carol : 5/7/2014<br>alopez : 12/18/2013<br>alopez : 12/17/2013<br>mgross : 11/6/2013<br>tkritzer : 2/10/2005<br>terry : 1/26/2005<br>mgross : 9/4/2002<br>alopez : 8/4/1998<br>alopez : 7/13/1998
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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>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
|
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<span class="mim-font">
|
|
<strong>*</strong> 602839
|
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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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|
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PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, DELTA; PIK3CD
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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>
|
|
<span class="mim-font">
|
|
PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, 110-KD, DELTA<br />
|
|
p110-DELTA<br />
|
|
PI3K-DELTA<br />
|
|
PIK3-DELTA
|
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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">
|
|
<strong><em>HGNC Approved Gene Symbol: PIK3CD</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> 711480000;
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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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<p>
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<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 1p36.22
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 1:9,627,258-9,729,114 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</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>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<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="3">
|
|
<span class="mim-font">
|
|
1p36.22
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
?Roifman-Chitayat syndrome, digenic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613328
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Digenic recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
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</tr>
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|
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|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Immunodeficiency 14A, autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
615513
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
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</tr>
|
|
|
|
|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Immunodeficiency 14B, autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
619281
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
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<div>
|
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<br />
|
|
</div>
|
|
|
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<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3-prime OH position of the inositol ring of inositol lipids. PIK3CD is a class I PI3K and displays a broad phosphoinositide lipid substrate specificity (Vanhaesebroeck et al., 1997). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>By RT-PCR of mRNA from a T-cell line with degenerate primers derived from conserved regions of PI3K catalytic core domains, Vanhaesebroeck et al. (1997) isolated a cDNA encoding a protein that they designated p110-delta. Sequence analysis revealed that the predicted 1,044-amino acid p110-delta protein is a PI3K that is 58% identical to p110-beta (602925). By Northern blot analysis of human tissues and immunolocalization in rat tissues, Vanhaesebroeck et al. (1997) found that p110-delta is selectively expressed in leukocytes. The p110-delta transcript is approximately 6 kb. </p><p>Independently, Seki et al. (1997) also cloned and characterized PIK3CD. </p><p>Chantry et al. (1997) isolated mouse and human p110-delta cDNAs. Sequence analysis revealed that the predicted proteins are 94% identical. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Clayton et al. (2001) determined that the mouse Pik3cd gene contains 22 exons and spans over 13 kb. Its exon structure most closely resembles that of Pik3cb. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Using FISH and radiation hybrid analysis, Seki et al. (1997) mapped the PIK3CD gene to chromosome 1p36.2, a region frequently lost in malignancy. </p><p>Clayton et al. (2001) suggested that the mouse Pik3d gene may be located on chromosome 4 in a region of syntenic homology with human chromosome 1p36.2-p32. </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Vanhaesebroeck et al. (1997) classified p110-delta as a class I PI3K because it displayed broad in vitro lipid substrate specificity. Like p110-alpha (PIK3CA; 171834) and p110-beta, p110-delta binds p85 adaptor proteins and GTP-bound Ras. These 3 class I PI3Ks were indistinguishable at the level of p85 adaptor protein selection or recruitment to activated receptor complexes. However, unlike p110-alpha, p110-delta does not phosphorylate p85, but instead has an autophosphorylation activity. </p><p>Zhang et al. (2002) noted that p110-delta had not detected in platelets. By examining human platelets, they found that p110-delta was highly susceptible to proteolytic degradation. Using Western blot, RT-PCR, activity, and immunoprecipitation analyses of lysed human platelets and detergent-insoluble cytoskeletal fractions from resting and thrombin receptor (F2R; 187930)-activated human platelets, Zhang et al. (2002) showed that p110-delta was present in association with p85-alpha (PIK3R1; 171833) and p85-beta (PIK3R2; 603157) in both cytosolic and cytoskeletal fractions of platelets. Zhang et al. (2002) proposed that cytoskeletal function in activated platelets and platelet spawning from megakaryocytes may be influenced by p110-delta. </p><p>Ali et al. (2004) reported that genetic or pharmacologic inactivation of the p110-delta isoform of PI(3)K in mast cells led to defective stem cell factor (SCF; 184745)-mediated in vitro proliferation, adhesion, and migration, and to impaired allergen-IgE (147180)-induced degranulation and cytokine release. Inactivation of p110-delta protected mice against anaphylactic allergic responses. </p><p>Ali et al. (2014) reported that p110-delta inactivation in mice protects against a broad range of cancers, including nonhematologic solid tumors, and demonstrated that p110-delta inactivation in regulatory T cells unleashes CD8+ cytotoxic T cells and induces tumor regression. Ali et al. (2014) concluded that p110-delta inhibitors can break tumor-induced immune tolerance. </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><strong><em>Autosomal Dominant Immunodeficiency 14A With Lymphoproliferation</em></strong></p><p>
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In 17 patients from 7 unrelated families with autosomal dominant primary immunodeficiency-14A (IMD14A; 615513), Angulo et al. (2013) identified the same heterozygous missense mutation (602839.0001) in the PIK3CD gene that resulted in a dominant gain of function. The E1021K mutation enhanced membrane association and kinase activity of p110-delta. Selective p110-delta inhibitors reduced the activity of the mutant enzyme in vitro, suggesting a therapeutic approach for these patients. </p><p>In a Taiwanese boy of Chinese descent with IMD14A, Jou et al. (2006) identified a heterozygous missense mutation in the PIK3CD gene (E1021K; 602839.0001). Functional studies of the variant were not performed. The PIK3CD gene was chosen for study because Pik3cd-null mice show a B-cell immunodeficiency; the patient was the only one of 15 probands with immunodeficiency who was found to carry a pathogenic PIK3CD mutation. </p><p>In 14 patients from 7 unrelated families with IMD14A, Lucas et al. (2014) identified 3 different heterozygous gain-of-function mutations in the PIK3CD gene (602839.0001-602839.0003). The mutations were found by whole-exome sequencing and targeted Sanger sequencing. Studies of patient-derived cells and control cells showed that the mutations caused increased phosphorylation of AKT (164730) compared to wildtype PIK3CD, consistent with a gain of function. Patient CD8+ T cells had an effector memory phenotype and were more activated compared to controls, suggesting that a large proportion of these cells are in a terminally differentiated state with a corresponding low proliferative capacity. Patient T cells showed hyperphosphorylation of the downstream mTOR (601231) signaling pathway, which resulted in increased glucose usage in the cells and predisposition to differentiation and senescence. Treatment of 1 patient with rapamycin, which inhibits mTOR, resulted in a reduction in CD8+ T cells to normal numbers and an increase in naive T cells. </p><p>In 3 patients from 2 unrelated families with IMD14A manifest as hyper-IgM and B-cell lymphoma, Crank et al. (2014) identified 2 heterozygous gain-of-function mutations in the PIK3CD gene (602839.0001 and 602839.0004). </p><p>Avery et al. (2018) studied a large cohort of patients with PIK3CD gain-of-function mutations and established a mouse model with a heterozygous activating Pik3cd mutation (E1020K, which is orthologous to the human E1021K mutation). In both species, hyperactivation of PI3K-dependent signaling pathways led to decreased mature B cells in bone marrow and in the periphery. Further analysis showed impaired Ig class switching, but no effect on proliferation and affinity maturation of B cells. Intrinsic defects in Ig class-switch recombination (CSR) in B-cell differentiation were caused by reduction in activation-induced cytidine deaminase (AID; 605257) expression in B cells and by failure to acquire a plasmablast gene signature and phenotype. These defects in B-cell differentiation could be partially overcome by treatment with a specific PIK3CD inhibitor, which restored CSR, AID expression, and Ig secretion. </p><p><strong><em>Roifman-Chitayat Syndrome</em></strong></p><p>
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In 2 sibs, born of consanguineous parents, with Roifman-Chitayat syndrome (ROCHIS; 613328) originally reported by Roifman and Chitayat (2009), Sharfe et al. (2018) identified homozygous loss-of-function mutations in 2 different genes: PIK3CD (602839.0005) and SKAP (KNSTRN; 614718.0001). The mutations, which were found by whole-genome sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed no detectable PIK3CD or KNSTRN proteins, consistent with a loss of function of both genes. Patient cells showed a near absence of AKT (164730) phosphorylation compared to controls, revealing defective PIK3CD function. Detailed in vitro studies showed that patient-derived B and T lymphocytes failed to cluster or aggregate properly, similar to abnormalities noted in SKAP-null cells, suggesting that SKAP deficiency was responsible for this feature. In addition, T cells showed reduced spontaneous migration and inefficient cell-cell contact formation due to limited cell spreading. These abnormalities were associated with aberrant MAP4 (157132) distribution and localized altered microtubule acetylation, which was attributed to loss of SKAP. Sharfe et al. (2018) concluded that the complex phenotype resulted from the concurrent loss of 2 different genes, each of which contributed to the disease manifestations. </p><p><strong><em>Autosomal Recessive Immunodeficiency 14B</em></strong></p><p>
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In 2 brothers, born of consanguineous Pakistani parents, with autosomal recessive immunodeficiency-14B (IMD14B; 619281), Sogkas et al. (2018) identified a homozygous frameshift mutation in the PIK3CD gene (602839.0006). The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient T cells showed impaired AKT phosphorylation after stimulation with an anti-CD3 antibody, suggesting a loss of PIK3CD function. </p><p>In a boy, born of consanguineous Pakistani parents, with IMD14B, Cohen et al. (2019) identified a homozygous frameshift mutation in the PIK3CD gene (602839.0007). The mutation, which was found by whole-exome sequencing, was predicted to disrupt the ATP binding site in the catalytic domain. The mutation was not found in the 1000 Genomes Project, ExAC, or Exome Sequencing Project databases. In vitro functional expression studies in HEK293T cells transfected with the mutation showed that the truncated protein was expressed, but lacked kinase activity, consistent with a loss of function. Patient T cells showed decreased calcium flux after CD3 stimulation compared to controls, suggesting impaired cellular immunity. Noting that dominant gain-of-function mutations in the PIK3CD gene can cause IMD14A, both Sogkas et al. (2018) and Cohen et al. (2019) concluded that precise regulation of PIK3CD activity is required for proper immune function. </p><p>Rodriguez et al. (2019) reported a 14-year-old boy, born of consanguineous Pakistani parents, with recurrent infections beginning in infancy who later developed chronic T-cell EBV infection with high EBV loads associated with hepatosplenomegaly and lymphadenopathies. At 14 years of age, he developed an acute episode of hemophagocytic lymphohistiocytosis (HLH) and died of the disease. His 6-year-old sister had an elevated blood EBV load in the absence of clinical symptoms. Whole-exome sequencing of the proband identified a homozygous frameshift variant (c.170delG) in the TNFRSF9 (CD137) gene (602250) that was also present in the homozygous state in his sister and in the heterozygous state in other unaffected family members. Studies of patient T cells showed lack of CD137 expression, suggesting that the variant results in a loss-of-function effect. Further studies identified a homozygous missense variant (R821H) in the PIK3CD gene that was present only in the proband; it was heterozygous in other family members, including the asymptomatic sister. The R821H variant was associated with reduced but residual kinase activity, consistent with a functional deficit. The authors suggested that CD137 deficiency likely accounts for the impaired immune control of EBV-infected T cells, whereas the mutation in the PIK3CD gene may act as a driver mutation allowing EBV-infected T cells to persist and proliferate uncontrollably. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Okkenhaug et al. (2002) generated mice expressing a catalytically inactive form of Pik3cd (asp910 to ala). They observed impaired signaling and attenuated immune responses by antigen receptors of B and T cells from these mice. The presence of Pik3ca and Pik3cb did not compensate for Pik3cd in immune function. The mutant mice also developed inflammatory bowel disease. Since the IBD7 susceptibility locus (605225) maps to chromosome 1p36, the authors suggested that PIK3CD may be a candidate susceptibility gene. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>7 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 IMMUNODEFICIENCY 14A WITH LYMPHOPROLIFERATION, AUTOSOMAL DOMINANT</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PIK3CD, GLU1021LYS
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<br />
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SNP: rs397518423,
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gnomAD: rs397518423,
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ClinVar: RCV000076908, RCV000224521, RCV001027610, RCV003224135, RCV004019089
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Taiwanese boy of Chinese descent with primary immunodeficiency-14A (IMD14A; 615513), Jou et al. (2006) identified a heterozygous G-to-A transition in exon 24 of the PIK3CD gene, resulting in a glu1021-to-lys (E1021K) substitution at a highly conserved residue in the catalytic domain. The mutation was not found in his parents or in 112 control individuals. Functional studies of the variant were not performed. The patient had had a primary B-cell deficiency with hypogammaglobulinemia and recurrent sinopulmonary infections since 7 months of age. The PIK3CD gene was chosen for study because Pik3cd-null mice show a B-cell immunodeficiency; the patient was the only one of 15 probands with immunodeficiency who was found to carry a pathogenic PIK3CD mutation. </p><p>In 17 individuals from 7 unrelated families with IMD14A, Angulo et al. (2013) identified a heterozygous G-to-A transition at nucleotide 3061 of the PIK3CD gene that resulted in a glutamic acid-to-lysine substitution at codon 1021 (E1021K) of the p110-delta protein. All affected individuals carried this mutation. This mutation was not identified among 3,346 healthy subjects. In 1 affected individual the mutation occurred as a de novo event; otherwise inheritance was autosomal dominant. The E1021K mutation in the catalytic subunit results in gain of function causing enhanced membrane association and kinase activity. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT (164730) protein and were prone to activation-induced cell death. </p><p>In 6 patients from 3 families with IMD14A, Lucas et al. (2014) identified a heterozygous E1021K mutation in the C-lobe of the kinase domain. The mutation was found by whole-exome sequencing and targeted Sanger sequencing. Structural analysis suggested that the E1021K substitution may enhance the recruitment of the protein to the plasma membrane and increase catalytic activity. </p><p>Crank et al. (2014) identified an E1021K mutation in a 21-year-old Caucasian woman with IMD14A who had increased serum IgM and developed a large B-cell lymphoma. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 IMMUNODEFICIENCY 14A WITH LYMPHOPROLIFERATION, AUTOSOMAL DOMINANT</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PIK3CD, ASN334LYS
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<br />
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SNP: rs28730670,
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gnomAD: rs28730670,
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ClinVar: RCV000119275
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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 12-year-old girl with autosomal dominant immunodeficiency-14A (IMD14A; 615513), Lucas et al. (2014) identified a heterozygous c.1002C-A transversion in the PIK3CD gene, resulting in an asn334-to-lys (N334K) substitution in the C2 domain. The mutation was found by whole-exome sequencing and targeted Sanger sequencing. Structural analysis suggested that the N334K substitution may disrupt inhibitory contacts between PIK3CD and the regulatory subunit (PIK3R1; 171833). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0003 IMMUNODEFICIENCY 14A WITH LYMPHOPROLIFERATION, AUTOSOMAL DOMINANT</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PIK3CD, GLU525LYS
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<br />
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SNP: rs587777389,
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ClinVar: RCV000119276, RCV004745195
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 7 patients from 3 families with autosomal dominant immunodeficiency-14A (IMD14A; 615513), Lucas et al. (2014) identified a heterozygous c.1573G-A transition in the PIK3CD gene, resulting in a glu525-to-lys (E525K) substitution in the helical domain. The mutation was found by whole-exome sequencing and targeted Sanger sequencing. Structural analysis suggested that the N334K substitution may disrupt inhibitory contacts between PIK3CD and the regulatory subunit (PIK3R1; 171833). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0004 IMMUNODEFICIENCY 14A WITH LYMPHOPROLIFERATION, AUTOSOMAL DOMINANT</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PIK3CD, CYS416ARG
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<br />
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SNP: rs587777390,
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ClinVar: RCV000119277
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 affected members of a family with autosomal dominant immunodeficiency-14A (IMD14A; 615513), Crank et al. (2014) identified a heterozygous c.1246T-C transition in the PIK3CD gene, resulting in a cys416-to-arg (C416R) substitution. The mutation was demonstrated to result in a gain of function with hyperphosphorylation of AKT (164730). Both patients had recurrent infections, lymphadenopathy, and increased serum IgM, and both developed B-cell lymphoma. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0005 ROIFMAN-CHITAYAT SYNDROME, DIGENIC (1 family)</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PIK3CD, GLN721TER
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<br />
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SNP: rs2100976217,
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ClinVar: RCV002246350
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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 2 sisters, born of consanguineous parents, with Roifman-Chitayat syndrome (ROCHIS; 613328) originally reported by Roifman and Chitayat (2009), Sharfe et al. (2018) identified a homozygous c.2161C-T transition in the PIK3CD gene, resulting in a gln721-to-ter (Q721X) substitution at the beginning of the kinase domain. The mutation, which was found by whole-genome sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed absence of the full-length protein, and near absence of AKT (164730) phosphorylation compared to controls, consistent with a loss of function. The patients were also homozygous for a loss-of-function mutation in the KNSTRN gene (614718.0001). Loss of both genes contributed to the phenotype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 IMMUNODEFICIENCY 14B, AUTOSOMAL RECESSIVE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PIK3CD, 1-BP DEL, 1653G
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<br />
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SNP: rs2100956273,
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ClinVar: RCV001374740
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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 2 brothers, born of consanguineous Pakistani parents, with autosomal recessive immunodeficiency-14B (IMD14B; 619281), Sogkas et al. (2018) identified a homozygous 1-bp deletion (c.1653delG) in the PIK3CD gene, resulting in a frameshift and premature termination (Val552SerfsTer26). The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient T cells showed impaired AKT phosphorylation after stimulation with an anti-CD3 antibody, suggesting a loss of PIK3CD function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0007 IMMUNODEFICIENCY 14B, AUTOSOMAL RECESSIVE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PIK3CD, 2-BP DEL, 2558AT
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<br />
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SNP: rs2100990445,
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ClinVar: RCV001374741
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a boy, born of consanguineous Pakistani parents, with autosomal recessive immunodeficiency-14B (IMD14B; 619281), Cohen et al. (2019) identified a homozygous 2-bp deletion (c.2558_2559delAT) in the PIK3CD gene, resulting in a frameshift and premature termination (Asp853GlyfsTer20). The mutation, which was found by whole-exome sequencing, was predicted to disrupt exons 20 to 24 encoding 171 residues of the ATP binding site in the catalytic domain. The mutation was not found in the 1000 Genomes Project, ExAC, or Exome Sequencing Project databases. In vitro functional expression studies in HEK293T cells transfected with the mutation showed that the truncated protein was expressed, but lacked kinase activity, consistent with a loss of function. Patient T cells showed decreased calcium flux after CD3 stimulation compared to controls, suggesting impaired cellular immunity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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Jou, S.-T., Chien, Y.-H., Yang, Y.-H., Wang, T.-C., Shyur, S.-D., Chou, C.-C., Chang, M.-L., Lin, D.-T., Lin, K.-H., Chiang, B.-L.
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Lucas, C. L., Kuehn, H. S., Zhao, F., Niemela, J. E., Deenick, E. K., Palendira, U., Avery, D. T., Moens, L., Cannons, J. L., Biancalana, M., Stoddard, J., Ouyang, W., and 16 others.
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<strong>Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110-delta result in T cell senescence and human immunodeficiency.</strong>
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Okkenhaug, K., Bilancio, A., Farjot, G., Priddle, H., Sancho, S., Peskett, E., Pearce, W., Meek, S. E., Salpekar, A., Waterfield, M. D., Smith, A. J. H., Vanhaesebroeck, B.
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<strong>Impaired B and T cell antigen receptor signaling in p110-delta PI 3-kinase mutant mice.</strong>
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Science 297: 1031-1034, 2002.
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Rodriguez, R., Fournier, B., Cordeiro, D. J., Winter, S., Izawa, K., Martin, E., Boutboul, D., Lenoir, C., Fraitag, S., Kracker, S., Watts, T. H., Picard, C., Bruneau, J., Callebaut, I., Fischer, A., Neven, B., Latour, S.
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<strong>Concomitant PIK3CD and TNFRSF9 deficiencies cause chronic active Epstein-Barr virus infection of T cells.</strong>
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J. Exp. Med. 216: 2800-2818, 2019.
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Roifman, C. M., Chitayat, D.
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<strong>Combined immunodeficiency, facial dysmorphism, optic nerve atrophy, skeletal anomalies and developmental delay: a new syndrome.</strong>
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Seki, N., Nimura, Y., Ohira, M., Saito, T., Ichimiya, S., Nomura, N., Nakagawara, A.
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Sharfe, N., Karanxha, A., Dadi, H., Merico, D., Chitayat, D., Herbrick, J.-A., Freeman, S., Grinstein, S., Roifman, C. M.
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Vanhaesebroeck, B., Welham, M. J., Kotani, K., Stein, R., Warne, P. H., Zvelebil, M. J., Higashi, K., Volinia, S., Downward, J., Waterfield, M. D.
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<p class="mim-text-font">
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Zhang, J., Vanhaesebroeck, B., Rittenhouse, S. E.
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<strong>Human platelets contain p110-delta phosphoinositide 3-kinase.</strong>
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<button type="button" id="mimDonationPopupDonate" class="btn btn-success btn-block" data-dismiss="modal"> Donate To OMIM! </button>
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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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</body>
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</html>
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