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Entry
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- *171833 - PHOSPHATIDYLINOSITOL 3-KINASE, REGULATORY SUBUNIT 1; PIK3R1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*171833</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="#geneFunction">Gene Function</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/171833">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=ENSG00000145675;t=ENST00000521381" 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=5295" 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=171833" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000145675;t=ENST00000521381" 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_001242466,NM_181504,NM_181523,NM_181524,XM_005248542,XM_017009585,XM_047417315,XM_047417316,XM_047417317" 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_181523" 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=171833" 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=01381&isoform_id=01381_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/PIK3R1" 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/1224073,21410090,27462174,32455248,32455250,32455252,62898958,66267557,118572681,119571696,119571697,119571698,193785156,193787728,221040434,221042876,335057534,400530116,400530118,530379378,1034645286,1403730432,2217356198,2217356201,2217356203,2462603012,2462603014,2462603016,2462603018" 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/P27986" 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=5295" 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=ENSG00000145675;t=ENST00000521381" 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=PIK3R1" 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=PIK3R1" 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+5295" 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/PIK3R1" 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:5295" 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/5295" 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=chr5&hgg_gene=ENST00000521381.6&hgg_start=68215756&hgg_end=68301821&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:8979" 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/pik3r1" 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=171833[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=171833[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/PIK3R1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000145675" 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=PIK3R1" 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=PIK3R1" 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=PIK3R1" 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=PIK3R1&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/PA33312" 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:8979" 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/FBgn0020622.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:97583" 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/PIK3R1#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:97583" 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/5295/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=5295" 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=WBGene00000001;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-030131-1280" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:5295" 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=PIK3R1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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171833
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
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<span class="mim-font">
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PHOSPHATIDYLINOSITOL 3-KINASE, REGULATORY SUBUNIT 1; PIK3R1
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</span>
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</h3>
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</div>
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<div>
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
PHOSPHATIDYLINOSITOL 3-KINASE-ASSOCIATED p85-ALPHA; GRB1<br />
|
|
PHOSPHATIDYLINOSITOL 3-KINASE, REGULATORY SUBUNIT, 85-KD, ALPHA<br />
|
|
p85-ALPHA
|
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</span>
|
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</h4>
|
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</div>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PIK3R1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PIK3R1</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/5/218?start=-3&limit=10&highlight=218">5q13.1</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr5:68215756-68301821&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'})">5:68,215,756-68,301,821</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=615214,616005,269880" 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/5/218?start=-3&limit=10&highlight=218">
|
|
5q13.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
?Agammaglobulinemia 7, autosomal recessive
|
|
|
|
<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>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/615214"> 615214 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
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</tr>
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|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Immunodeficiency 36
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/616005"> 616005 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<p>Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates the inositol ring of phosphatidylinositol and related compounds at the 3-prime position. The products of these reactions are thought to serve as second messengers in growth signaling pathways. The kinase itself is made up of a catalytic subunit of molecular mass 110 kD (p110; e.g., PIK3CA, <a href="/entry/171834">171834</a>) and a regulatory subunit, often of molecular mass 85 kD (p85), such as PIK3R1 (summary by <a href="#18" class="mim-tip-reference" title="Hoyle, J., Yulug, I. G., Egan, S. E., Fisher, E. M. C. <strong>The gene that encodes the phosphatidylinositol-3 kinase regulatory subunit (p85-alpha) maps to chromosome 13 in the mouse.</strong> Genomics 24: 400-402, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7698770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7698770</a>] [<a href="https://doi.org/10.1006/geno.1994.1638" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7698770">Hoyle et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7698770" 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="#25" class="mim-tip-reference" title="Otsu, M., Hiles, I., Gout, I., Fry, M. J., Ruiz-Larrea, F., Panayotou, G., Thompson, A., Dhand, R., Hsuan, J., Totty, N., Smith, A. D., Morgan, S. J., Courtneidge, S. A., Parker, P. J., Waterfield, M. D. <strong>Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60(c-src) complexes, and PI3-kinase.</strong> Cell 65: 91-104, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1707345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1707345</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90411-q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1707345">Otsu et al. (1991)</a> showed that the bovine PI3K p85 subunit consists of 2 closely related proteins, p85-alpha and p85-beta (PIK3R2; <a href="/entry/603157">603157</a>). They cloned cDNAs encoding both p85 subunits, each of which is a 724-amino acid polypeptide. The 2 subunits shared 62% amino acid sequence identity across their entire length. Both sequences contained an N-terminal SH3 region, 2 SH2 regions, and a region of homology to the C-terminal region of BCR (<a href="/entry/151410">151410</a>). Functional expression studies showed that both p85 subunits lacked PI3-kinase activity, but both bound to tyrosine kinase receptors. <a href="#36" class="mim-tip-reference" title="Volinia, S., Patracchini, P., Otsu, M., Hiles, I., Gout, I., Calzolari, E., Bernardi, F., Rooke, L., Waterfield, M. D. <strong>Chromosomal localization of human p85-alpha, a subunit of phosphatidylinositol 3-kinase, and its homologue p85-beta.</strong> Oncogene 7: 789-793, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1314371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1314371</a>]" pmid="1314371">Volinia et al. (1992)</a> stated that human p85-alpha contains all the peptide sequence found in bovine p85-alpha. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1707345+1314371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Skolnik, E. Y., Margolis, B., Mohammadi, M., Lowenstein, E., Fischer, R., Drepps, A., Ullrich, A., Schlessinger, J. <strong>Cloning of PI3-kinase associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases.</strong> Cell 65: 83-90, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1849461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1849461</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90410-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1849461">Skolnik et al. (1991)</a> developed a novel method for expression cloning of receptor tyrosine kinase target proteins (called CORT for 'cloning of receptor targets') and illustrated the method by cloning cDNA for GRB1, the gene encoding phosphatidylinositol 3-kinase-associated p85-alpha. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1849461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The PIK3R1 gene encodes 3 regulatory isoforms of PI3K: p85, p55, and p50. The 9 3-prime exons are shared by all 3 isoforms with 2 distinct promoters, and 2 exon 1 sequences upstream of these 9 exons control the production of p55 and p50 (summary by <a href="#9" class="mim-tip-reference" title="Conley, M. E., Dobbs, A. K., Quintana, A. M., Bosompem, A., Wang, Y.-D., Coustan-Smith, E., Smith, A. M., Perez, E. E., Murray, P. J. <strong>Agammaglobulinemia and absent B lineage cells in a patient lacking the p85-alpha subunit of PI3K.</strong> J. Exp. Med. 209: 463-470, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22351933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22351933</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22351933[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.20112533" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22351933">Conley et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22351933" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Conley, M. E., Dobbs, A. K., Quintana, A. M., Bosompem, A., Wang, Y.-D., Coustan-Smith, E., Smith, A. M., Perez, E. E., Murray, P. J. <strong>Agammaglobulinemia and absent B lineage cells in a patient lacking the p85-alpha subunit of PI3K.</strong> J. Exp. Med. 209: 463-470, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22351933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22351933</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22351933[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.20112533" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22351933">Conley et al. (2012)</a> found variable expression of the 3 regulatory isoforms in hematopoietic cells: normal T cells expressed almost equal amounts of p85 and p50, and activated T cells also contained trace amounts of p55. In contrast, normal B cells contained p85, but no detectable p50 or p55; EBV-transformed B cells expressed low levels of p50 and p55. NK cells and neutrophils contained p85 and low levels of p50. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22351933" 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="#31" class="mim-tip-reference" title="Skolnik, E. Y., Margolis, B., Mohammadi, M., Lowenstein, E., Fischer, R., Drepps, A., Ullrich, A., Schlessinger, J. <strong>Cloning of PI3-kinase associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases.</strong> Cell 65: 83-90, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1849461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1849461</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90410-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1849461">Skolnik et al. (1991)</a> showed that the product of the GRB1 gene associates with activated growth factor receptors. p85-alpha modulates the interaction between PI3 kinase and platelet-derived growth factor receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1849461" 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="#30" class="mim-tip-reference" title="Simoncini, T., Hafezi-Moghadam, A., Brazil, D. P., Ley, K., Chin, W. W., Liao, J. K. <strong>Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase.</strong> Nature 407: 538-541, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11029009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11029009</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11029009[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/10.1038/35035131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11029009">Simoncini et al. (2000)</a> showed that the estrogen receptor isoform ER-alpha (<a href="/entry/133430">133430</a>) binds in a ligand-dependent manner to the p85-alpha regulatory subunit of PI3K. Stimulation with estrogen increases ER-alpha-associated PI3K activity, leading to the activation of protein kinase B/AKT (<a href="/entry/164730">164730</a>) and endothelial nitric oxide synthase (eNOS; <a href="/entry/163729">163729</a>). Recruitment and activation of PI3K by ligand-bound ER-alpha are independent of gene transcription, do not involve phosphotyrosine adaptor molecules or src-homology domains of p85-alpha, and extend to other steroid hormone receptors. Mice treated with estrogen showed increased eNOS activity and decreased vascular leukocyte accumulation after ischemia and reperfusion injury. This vascular protective effect of estrogen was abolished in the presence of PI3K or eNOS inhibitors. <a href="#30" class="mim-tip-reference" title="Simoncini, T., Hafezi-Moghadam, A., Brazil, D. P., Ley, K., Chin, W. W., Liao, J. K. <strong>Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase.</strong> Nature 407: 538-541, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11029009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11029009</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11029009[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/10.1038/35035131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11029009">Simoncini et al. (2000)</a> concluded that their findings defined a physiologically important nonnuclear estrogen-signaling pathway involving the direct interaction of ER-alpha with PI3K. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11029009" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Niswender, K. D., Morton, G. J., Stearns, W. H., Rhodes, C. J., Myers, M. G., Jr., Schwartz, M. W. <strong>Key enzyme in leptin-induced anorexia.</strong> Nature 413: 794-795, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11677594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11677594</a>] [<a href="https://doi.org/10.1038/35101657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11677594">Niswender et al. (2001)</a> demonstrated that systemic administration of leptin (<a href="/entry/164160">164160</a>) in rat activates the enzyme phosphatidylinositol-3-hydroxykinase in the hypothalamus and that intracerebroventricular infusion of inhibitors of this enzyme prevents leptin-induced anorexia. They concluded that phosphatidylinositol-3-hydroxykinase is a crucial enzyme in the signal transduction pathway that links hypothalamic leptin to reduced food intake. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11677594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="He, Y., Nakao, H., Tan, S.-L., Polyak, S. J., Neddermann, P., Vijaysri, S., Jacobs, B. L., Katze, M. G. <strong>Subversion of cell signaling pathways by hepatitis C virus nonstructural 5A protein via interaction with Grb2 and P85 phosphatidylinositol 3-kinase.</strong> J. Virol. 76: 9207-9217, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12186904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12186904</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12186904[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/jvi.76.18.9207-9217.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12186904">He et al. (2002)</a> determined that the hepatitis C virus nonstructural 5A (NS5A) protein interacts directly with GRB2 (<a href="/entry/108355">108355</a>) and with the p85 subunit of PI3K following stimulation with epidermal growth factor (EGF; <a href="/entry/131530">131530</a>). The in vivo association of NS5A with p85 PI3K increased tyrosine phosphorylation of p85 PI3K. Downstream effects of the EGF-induced interaction included tyrosine phosphorylation of AKT and serine phosphorylation of BAD (<a href="/entry/603167">603167</a>). Both of these events would tend to inhibit apoptosis and were consistent with the antiapoptotic properties of NS5A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12186904" 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>Ectopic activation of fibroblast growth factor receptor-3 (FGFR3; <a href="/entry/134934">134934</a>) is associated with several cancers, including multiple myeloma (<a href="/entry/254500">254500</a>). <a href="#29" class="mim-tip-reference" title="Salazar, L., Kashiwada, T., Krejci, P., Muchowski, P., Donoghue, D., Wilcox, W. R., Thompson, L. M. <strong>A novel interaction between fibroblast growth factor receptor 3 and the p85 subunit of phosphoinositide 3-kinase: activation-dependent regulation of ERK by p85 in multiple myeloma cells.</strong> Hum. Molec. Genet. 18: 1951-1961, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19286672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19286672</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19286672[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19286672">Salazar et al. (2009)</a> identified the PI3K regulatory subunit PIK3R1 as a novel interactor of FGFR3 by yeast 2-hybrid screen and confirmed an interaction between FGFR3 and PIK3R1 and PIK3R2 in mammalian cells. The interaction of FGFR3 with PIK3R1 was dependent upon receptor activation. In contrast to the Gab1 (<a href="/entry/604439">604439</a>)-mediated association of FGFRs with PIK3R1, the FGFR3-PIK3R1 interaction required FGFR3 tyr760, previously identified as a PLC-gamma (PLCG1; <a href="/entry/172420">172420</a>)-binding site. Interaction of PIK3R1 with FGFR3 did not require PLC-gamma, suggesting that PIK3R1 interaction was direct and independent of PLC-gamma binding. FGFR3 and PIK3R1/PIK3R2 proteins also interacted in multiple myeloma cell lines, which consistently express PIK3R1 p85 isoforms but not p50 or p55 isoforms, or PIK3R3 (<a href="/entry/606076">606076</a>). siRNA knockdown of PIK3R2 in multiple myeloma cells caused an increased ERK response to FGF2 stimulation. <a href="#29" class="mim-tip-reference" title="Salazar, L., Kashiwada, T., Krejci, P., Muchowski, P., Donoghue, D., Wilcox, W. R., Thompson, L. M. <strong>A novel interaction between fibroblast growth factor receptor 3 and the p85 subunit of phosphoinositide 3-kinase: activation-dependent regulation of ERK by p85 in multiple myeloma cells.</strong> Hum. Molec. Genet. 18: 1951-1961, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19286672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19286672</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19286672[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19286672">Salazar et al. (2009)</a> suggested that an endogenous negative regulatory role for the PIK3R-FGFR3 interaction on the Ras/ERK/MAPK pathway may exist in response to FGFR3 activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19286672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using mouse embryonic fibroblasts, <a href="#26" class="mim-tip-reference" title="Park, S. W., Zhou, Y., Lee, J., Lu, A., Sun, C., Chung, J., Ueki, K., Ozcan, U. <strong>The regulatory subunits of PI3K, p85-alpha and p85-beta, interact with XBP-1 and increase its nuclear translocation.</strong> Nature Med. 16: 429-437, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20348926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20348926</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20348926[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/nm.2099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20348926">Park et al. (2010)</a> showed that, in addition to regulating PI3K function, p85-alpha and p85-beta regulated the function of Xbp1s (XBP1; <a href="/entry/194355">194355</a>), a transcription factor that orchestrates the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress. Both p85-alpha and p85-beta bound Xbp1s and increased its nuclear translocation, and it appeared that the p110 PI3K catalytic subunit and Xbp1s competed for binding of these regulatory subunits. p85-alpha and p85-beta formed an inactive dimer that was disrupted by insulin in a time-dependent manner, which promoted their association with Xbp1s. Refeeding of wildtype mice after fasting induced ER stress that was quickly resolved, as measured by Xbp1s levels. In contrast, obese and insulin-resistant ob/ob (LEP; <a href="/entry/164160">164160</a>) mice could not resolve the ER stress induced during refeeding, and nuclear translocation of Xbp1s was absent in ob/ob mice. Overexpression of p85-alpha or p85-beta in livers of ob/ob mice increased glucose tolerance and reduced blood glucose concentrations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20348926" 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="#37" class="mim-tip-reference" title="Winnay, J. N., Boucher, J., Mori, M. A., Ueki, K., Kahn, C. R. <strong>A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box-binding protein-1 to modulate the unfolded protein response.</strong> Nature Med. 16: 438-445, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20348923/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20348923</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20348923[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/nm.2121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20348923">Winnay et al. (2010)</a> found that p85-alpha interacted with Xbp1 in an ER stress-dependent manner in mice and that this interaction was essential in the ER stress response. Cells deficient in p85-alpha or mouse livers with selective inactivation of p85-alpha showed reduced ER stress-dependent accumulation of nuclear Xbp1s and attenuated induction of UPR target genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20348923" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using yeast 2-hybrid analysis, pull-down assays, and immunofluorescence analysis, <a href="#7" class="mim-tip-reference" title="Chiu, Y.-H., Lee, J. Y., Cantley, L. C. <strong>BRD7, a tumor suppressor, interacts with p85-alpha and regulates PI3K activity.</strong> Molec. Cell 54: 193-202, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24657164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24657164</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24657164[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.molcel.2014.02.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24657164">Chiu et al. (2014)</a> found that human BRD7 (<a href="/entry/618489">618489</a>) interacted with p85-alpha and induced its nuclear translocation. Formation of the BRD7-p85-alpha complex depended on a p85-binding domain in the highly conserved C terminus of BRD7, whereas the nuclear localization of the BRD7-p85-alpha complex depended on the nuclear localization signal of BRD7. The BRD7-p85-alpha complex associated with chromatin. The BRD7-binding region of p85-alpha was the same region used for interaction with p110. Consequently, BRD7 competed with p110 for binding and interacted with free p85-alpha, but not with p85/p110 complexes, and BRD7 did not translocate p110 into the nucleus with BRD7. BRD7 removed p85-alpha from the cytosol to prevent formation of the p85/p110 complex, thereby destabilizing p110 proteins and reducing PI3K signaling. Knockdown of BRD7 increased p110 protein levels, decreased the fraction of p85-alpha in nucleus, and enhanced PI3K signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24657164" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#22" class="mim-tip-reference" title="Miled, N., Yan, Y., Hon, W.-C., Perisic, O., Zvelebil, M., Inbar, Y., Schneidman-Duhovny, D., Wolfson, H. J., Backer, J. M., Williams, R. L. <strong>Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit.</strong> Science 317: 239-242, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17626883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17626883</a>] [<a href="https://doi.org/10.1126/science.1135394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17626883">Miled et al. (2007)</a> used crystallographic and biochemical approaches to gain insight into activating mutations in 2 noncatalytic p100-alpha domains--the adaptor-binding and the helical domains. A structure of the adaptor-binding domain of p110-alpha (<a href="/entry/171834">171834</a>) in a complex with the p85-alpha inter-Src homology 2 (inter-SH2) domains shows that the oncogenic mutations in the adaptor-binding domain are not at the inter-SH2 interface but in a polar surface patch that is a plausible docking site for other domains in the holo p110/p85 complex. The authors also examined helical domain mutations and found that the glu545-to-lys (E545K) oncogenic mutant disrupts an inhibitory charge-charge interaction with the p85 N-terminal SH2 domain. <a href="#22" class="mim-tip-reference" title="Miled, N., Yan, Y., Hon, W.-C., Perisic, O., Zvelebil, M., Inbar, Y., Schneidman-Duhovny, D., Wolfson, H. J., Backer, J. M., Williams, R. L. <strong>Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit.</strong> Science 317: 239-242, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17626883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17626883</a>] [<a href="https://doi.org/10.1126/science.1135394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17626883">Miled et al. (2007)</a> concluded that their studies extended understanding of the architecture of the phosphatidylinositol 3-kinases and provided insight into how 2 classes of mutations that cause a gain of function can lead to cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17626883" 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="Cannizzaro, L. A., Skolnik, E. Y., Margolis, B., Croce, C. M., Schlesinger, J., Huebner, K. <strong>The human gene encoding phosphatidylinositol 3-kinase associated p85-alpha is at chromosome region 5q12-13.</strong> Cancer Res. 51: 3818-3820, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1648445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1648445</a>]" pmid="1648445">Cannizzaro et al. (1991)</a> demonstrated that the GRB1 gene is located at 5q13 by analysis of its segregation in rodent-human hybrids and by chromosome in situ hybridization. <a href="#6" class="mim-tip-reference" title="Cannizzaro, L. A., Skolnik, E. Y., Margolis, B., Croce, C. M., Schlesinger, J., Huebner, K. <strong>The human gene encoding phosphatidylinositol 3-kinase associated p85-alpha is at chromosome region 5q12-13.</strong> Cancer Res. 51: 3818-3820, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1648445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1648445</a>]" pmid="1648445">Cannizzaro et al. (1991)</a> observed that the RASA gene (<a href="/entry/139150">139150</a>), encoding another receptor-associated signal transducing protein, is also located in 5q13. <a href="#36" class="mim-tip-reference" title="Volinia, S., Patracchini, P., Otsu, M., Hiles, I., Gout, I., Calzolari, E., Bernardi, F., Rooke, L., Waterfield, M. D. <strong>Chromosomal localization of human p85-alpha, a subunit of phosphatidylinositol 3-kinase, and its homologue p85-beta.</strong> Oncogene 7: 789-793, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1314371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1314371</a>]" pmid="1314371">Volinia et al. (1992)</a> confirmed the mapping of PIK3R1 to chromosome 5q12-q13. <a href="#18" class="mim-tip-reference" title="Hoyle, J., Yulug, I. G., Egan, S. E., Fisher, E. M. C. <strong>The gene that encodes the phosphatidylinositol-3 kinase regulatory subunit (p85-alpha) maps to chromosome 13 in the mouse.</strong> Genomics 24: 400-402, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7698770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7698770</a>] [<a href="https://doi.org/10.1006/geno.1994.1638" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7698770">Hoyle et al. (1994)</a> demonstrated that the homologous gene in the mouse, Pik3r1, maps to chromosome 13. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1648445+7698770+1314371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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In a patient with autosomal recessive agammaglobulinemia-7 (AGM7; <a href="/entry/615214">615214</a>), <a href="#9" class="mim-tip-reference" title="Conley, M. E., Dobbs, A. K., Quintana, A. M., Bosompem, A., Wang, Y.-D., Coustan-Smith, E., Smith, A. M., Perez, E. E., Murray, P. J. <strong>Agammaglobulinemia and absent B lineage cells in a patient lacking the p85-alpha subunit of PI3K.</strong> J. Exp. Med. 209: 463-470, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22351933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22351933</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22351933[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.20112533" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22351933">Conley et al. (2012)</a> identified a homozygous truncating variant in the PIK3R1 gene (W298X; <a href="#0001">171833.0001</a>). The mutation, which was identified by exome sequencing, segregated with the disorder and was not found in 1,000 in-house control alleles. Screening of the PIK3R1 gene in 55 additional patients with defects in B-cell development did not identify any other mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22351933" 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>SHORT Syndrome, Autosomal Dominant</em></strong></p><p>
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By whole-exome sequencing in 2 unrelated patients with SHORT syndrome (<a href="/entry/269880">269880</a>), <a href="#35" class="mim-tip-reference" title="Thauvin-Robinet, C., Auclair, M., Duplomb, L., Caron-Debarle, M., Avila, M., St-Onge, J., Le Merrer, M., Le Luyer, B., Heron, D., Mathieu-Dramard, M., Bitoun, P., Petit, J.-M., and 16 others. <strong>PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.</strong> Am. J. Hum. Genet. 93: 141-149, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23810378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23810378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23810378[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23810378">Thauvin-Robinet et al. (2013)</a> identified de novo mutations in the PIK3R1 gene (<a href="#0002">171833.0002</a> and <a href="#0003">171833.0003</a>). Screening PIK3R1 for mutations in 4 more affected individuals from 3 families revealed a recurrent substitution (R649W; <a href="#0004">171833.0004</a>) in all 4 patients. Sequencing PIK3R1 in a heterogeneous clinical group of 14 additional unrelated individuals with severe insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation, who had not previously been diagnosed with SHORT syndrome and who were negative for mutation in known lipodystrophy-associated genes, identified 3 with mutations in PIK3R1, including 1 with the recurrent R649W substitution and another with a 1-bp duplication at R649 (<a href="#0005">171833.0005</a>). <a href="#35" class="mim-tip-reference" title="Thauvin-Robinet, C., Auclair, M., Duplomb, L., Caron-Debarle, M., Avila, M., St-Onge, J., Le Merrer, M., Le Luyer, B., Heron, D., Mathieu-Dramard, M., Bitoun, P., Petit, J.-M., and 16 others. <strong>PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.</strong> Am. J. Hum. Genet. 93: 141-149, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23810378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23810378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23810378[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23810378">Thauvin-Robinet et al. (2013)</a> noted that the c.1945C-T (R649W) mutation occurred within the context of a CpG dinucleotide, which might explain its recurrence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23810378" 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 3-generation Norwegian family and in a German mother and son with SHORT syndrome, <a href="#8" class="mim-tip-reference" title="Chudasama, K. K., Winnay, J., Johansson, S., Claudi, T., Konig, R., Haldorsen, I., Johansson, B., Woo, J. R., Aarskog, D., Sagen, J. V., Kahn, C. R., Molven, A., Njolstad, P. R. <strong>SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling.</strong> Am. J. Hum. Genet. 93: 150-157, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23810379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23810379</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23810379[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23810379">Chudasama et al. (2013)</a> identified heterozygosity for the R649W missense mutation in the PIK3R1 gene. Haplotype analysis showed that the mutations resided on different backgrounds in the 2 families, indicating that they stemmed from 2 independent mutational events. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23810379" 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="Dyment, D. A., Smith, A. C., Alcantara, D., Schwartzentruber, J. A., Basel-Vanagaite, L., Curry, C. J., Temple, I. K., Reardon, W., Mansour, S., Haq, M. R., Gilbert, R., Lehmann, O. J., Vanstone, M. R., Beaulieu, C. L., FORGE Canada Consortium, Majewski, J., Bulman, D. E., O'Driscoll, M., Boycott, K. M., Innes, A. M. <strong>Mutations in PIK3R1 cause SHORT syndrome.</strong> Am. J. Hum. Genet. 93: 158-166, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23810382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23810382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23810382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.06.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23810382">Dyment et al. (2013)</a> performed whole-exome sequencing in a girl with SHORT syndrome and her unaffected parents and identified a frameshift mutation in the PIK3R1 gene (<a href="#0006">171833.0006</a>) that segregated with disease. Analysis of PIK3R1 in 3 more SHORT probands revealed the presence of the R649W mutation in an affected mother and 2 sons from an English family and in another patient. A PIK3R1 nonsense mutation was identified in the third patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23810382" 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>Immunodeficiency 36 With Lymphoproliferation, Autosomal Dominant</em></strong></p><p>
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In 4 patients from 3 unrelated families with autosomal dominant immunodeficiency-36 with lymphoproliferation (IMD36; <a href="/entry/616005">616005</a>), <a href="#11" class="mim-tip-reference" title="Deau, M.-C., Heurtier, L., Frange, P., Suarez, F., Bole-Feysot, C., Nitschke, P., Cavazzana, M., Picard, C., Durandy, A., Fischer, A., Kracker, S. <strong>A human immunodeficiency caused by mutations in the PIK3R1 gene.</strong> J. Clin. Invest. 124: 3923-3928, 2014. Note: Erratum: J. Clin. Invest. 125: 1764 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25133428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25133428</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25133428[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI75746" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25133428">Deau et al. (2014)</a> identified heterozygous mutations in the PIK3R1 gene (<a href="#0007">171833.0007</a> and <a href="#0008">171833.0008</a>). The mutations, which were found by whole-exome sequencing, affected the same nucleotide and resulted in the same splicing defect. The mutations were predicted to cause a loss of p85-mediated inhibition of p110 activity, and patient lymphocytes showed increased PI3K activity and enhanced phosphorylation of AKT, consistent with a gain of function. The phenotype was similar to that of patients with IMD14 (<a href="/entry/615513">615513</a>) carrying gain-of-function mutations in the PIK3CD gene (<a href="/entry/602839">602839</a>). Patients had decreased amounts of naive T cells and memory B cells, as well as hypogammaglobulinemia. The findings suggested that PI3K activity is tightly regulated in T and B lymphocytes and that various defects in the PI3K-triggered pathway can cause primary immunodeficiencies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25133428" 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 4 patients from 3 unrelated families with immunodeficiency, <a href="#21" class="mim-tip-reference" title="Lucas, C. L., Zhang, Y., Venida, A., Wang, Y., Hughes, J., McElwee, J., Butrick, M., Matthews, H., Price, S., Biancalana, M., Wang, X., Richards, M., Pozos, T., Barlan, I., Ozen, A., Rao, V. K., Su, H. C., Lenardo, M. J. <strong>Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.</strong> J. Exp. Med. 211: 2537-2547, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25488983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25488983</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25488983[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.20141759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25488983">Lucas et al. (2014)</a> identified heterozygosity for point mutations in the PIK3R1 gene at the same splice donor site that was previously reported in immunodeficient patients by <a href="#11" class="mim-tip-reference" title="Deau, M.-C., Heurtier, L., Frange, P., Suarez, F., Bole-Feysot, C., Nitschke, P., Cavazzana, M., Picard, C., Durandy, A., Fischer, A., Kracker, S. <strong>A human immunodeficiency caused by mutations in the PIK3R1 gene.</strong> J. Clin. Invest. 124: 3923-3928, 2014. Note: Erratum: J. Clin. Invest. 125: 1764 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25133428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25133428</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25133428[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI75746" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25133428">Deau et al. (2014)</a>: c.1425+1G-C (<a href="#0008">171833.0008</a>) in 3 patients from 2 families, and c.1425+1G-A (<a href="#0009">171833.0009</a>) in the remaining proband. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25488983+25133428" 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 4 unrelated children with immunodeficiency and a hyper-IGM (see <a href="/entry/308230">308230</a>)-like phenotype, who also exhibited poor growth and lymphoproliferation, <a href="#20" class="mim-tip-reference" title="Lougaris, V., Faletra, F., Lanzi, G., Vozzi, D., Marcuzzi, A., Valencic, E., Piscianz, E., Bianco, A., Girardelli, M., Baronio, M., Loganes, C., Fasth, A., Salvini, F., Trizzino, A., Moratto, D., Facchetti, F., Giliani, S., Plebani, A., Tommasini, A. <strong>Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype. (Letter)</strong> Clin. Immun. 159: 33-36, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25939554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25939554</a>] [<a href="https://doi.org/10.1016/j.clim.2015.04.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25939554">Lougaris et al. (2015)</a> identified heterozygosity for de novo mutations in the PIK3R1 gene at the same previously reported splice site, c.1425+1G (see <a href="#0007">171833.0007</a> and <a href="#0009">171833.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25939554" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Petrovski, S., Parrott, R. E., Roberts, J. L., Huang, H., Yang, J., Gorentla, B., Mousallem, T., Wang, E., Armstrong, M., McHale, D., MacIver, N. J., Goldstein, D. B., Zhong, X.-P., Buckley, R. H. <strong>Dominant splice site mutations in PIK3R1 cause hyper IgM syndrome, lymphadenopathy and short stature.</strong> J. Clin. Immun. 36: 462-471, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27076228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27076228</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27076228[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/10.1007/s10875-016-0281-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27076228">Petrovski et al. (2016)</a> reported 4 unrelated children with immunodeficiency and elevated IgM levels, lymphadenopathy, and short stature, who all carried the c.1425+1G-A mutation in the PIK3R1 gene (<a href="#0009">171833.0009</a>). One of the patients exhibited features of SHORT syndrome; the authors noted that no results of immune studies had been reported for SHORT syndrome patients. Functional analysis showed that the splice site mutation results in deletion of exon 11 and constitutive activation of PI3K signaling. The authors noted that despite the limited allelic heterogeneity, there was considerable phenotypic heterogeneity in clinical and immunologic abnormalities in patients with PIK3R1-associated immunodeficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27076228" 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="#13" class="mim-tip-reference" title="Elkaim, E., Neven, B., Bruneau, J., Mitsui-Sekinaka, K., Stanislas, A., Heurtier, L., Lucas, C. L., Matthews, H., Deau, M.-C., Sharapova, S., Curtis, J., Reichenbach, J., and 31 others. <strong>Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study.</strong> J. Allergy Clin. Immun. 138: 210-218, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27221134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27221134</a>] [<a href="https://doi.org/10.1016/j.jaci.2016.03.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27221134">Elkaim et al. (2016)</a> studied 36 patients with PIK3R1-associated immunodeficiency, including 8 previously reported patients (<a href="#11" class="mim-tip-reference" title="Deau, M.-C., Heurtier, L., Frange, P., Suarez, F., Bole-Feysot, C., Nitschke, P., Cavazzana, M., Picard, C., Durandy, A., Fischer, A., Kracker, S. <strong>A human immunodeficiency caused by mutations in the PIK3R1 gene.</strong> J. Clin. Invest. 124: 3923-3928, 2014. Note: Erratum: J. Clin. Invest. 125: 1764 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25133428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25133428</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25133428[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI75746" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25133428">Deau et al., 2014</a>; <a href="#21" class="mim-tip-reference" title="Lucas, C. L., Zhang, Y., Venida, A., Wang, Y., Hughes, J., McElwee, J., Butrick, M., Matthews, H., Price, S., Biancalana, M., Wang, X., Richards, M., Pozos, T., Barlan, I., Ozen, A., Rao, V. K., Su, H. C., Lenardo, M. J. <strong>Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.</strong> J. Exp. Med. 211: 2537-2547, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25488983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25488983</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25488983[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.20141759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25488983">Lucas et al., 2014</a>), and noted that the previously described substitutions at c.1425+1 were detected in 84% of patients, with G-A identified in 42%, G-C in 29%, and G-T in 13%. Four additional patients had mutations involving c.1425+2, including 2 with a T-A substitution (<a href="#0010">171833.0010</a>), 1 with a T-G substitution (<a href="#0011">171833.0011</a>), and 1 with a TG deletion (<a href="#0012">171833.0012</a>). Another patient had a G-C substitution at the -1 position of the splice acceptor site of exon 11 (<a href="#0013">171833.0013</a>). Analysis of patient mRNA demonstrated that all of the mutations cause skipping of exon 11 (coding exon 10). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25488983+27221134+25133428" 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>Associations Pending Confirmation</em></strong></p><p>
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Phosphatidylinositol 3-kinase is a key step in the metabolic actions of insulin. Two amino acid polymorphisms have been identified in the regulatory subunit of p85-alpha, met326 to ile and asn330 to asp. The former is associated with alterations in glucose/insulin homeostasis. <a href="#2" class="mim-tip-reference" title="Almind, K., Delahaye, L., Hansen, T., Van Obberghen, E., Pedersen, O., Kahn, C. R. <strong>Characterization of the Met326Ile variant of phosphatidylinositol 3-kinase p85-alpha.</strong> Proc. Nat. Acad. Sci. 99: 2124-2128, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11842213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11842213</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11842213[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.042688799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11842213">Almind et al. (2002)</a> presented observations indicating that the met326-to-ile variant of p85-alpha is functional for intracellular signaling and adipocyte differentiation but has small alterations in protein expression and activity that could play a role in modifying insulin action. These conclusions were based on studies where the 4 human p85-alpha proteins encoded by these 4 alleles were expressed in yeast. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11842213" 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>Somatic Mutations</em></strong></p><p>
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The <a href="#5" class="mim-tip-reference" title="Cancer Genome Atlas Research Network. <strong>Comprehensive genomic characterization defines human glioblastoma genes and core pathways.</strong> Nature 455: 1061-1068, 2008. Note: Erratum: Nature 494: 506 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18772890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18772890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18772890[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/nature07385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18772890">Cancer Genome Atlas Research Network (2008)</a> reported the interim integrative analysis of DNA copy number, gene expression, and DNA methylation aberrations in 206 glioblastomas and nucleotide sequence alterations in 91 of the 206 glioblastomas. The authors observed that the RTK/RAS/PI3K signaling pathway was altered in 88% of glioblastomas. Somatic mutation in the PI3K complex was frequently identified. In particular, novel somatic mutations were identified in the PIK3R1 gene that resulted in disruption of the important C2-iSH2 interaction between PIK3R1 and PIK3CA (<a href="/entry/171834">171834</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18772890" 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>Phosphoinositide 3-kinase (PI3K) activation is implicated in many responses, including fibroblast growth, transformation, survival, and chemotaxis. Although PI3K is activated by several agents that stimulate T and B cells, the role of PI3K in lymphocyte function remained to be clarified. <a href="#14" class="mim-tip-reference" title="Fruman, D. A., Snapper, S. B., Yballe, C. M., Davidson, L., Yu, J. Y., Alt, F. W., Cantley, L. C. <strong>Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85-alpha.</strong> Science 283: 393-397, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9888855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9888855</a>] [<a href="https://doi.org/10.1126/science.283.5400.393" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9888855">Fruman et al. (1999)</a> disrupted the mouse gene encoding the PI3K adaptor subunit p85-alpha and its splice variants p55-alpha and p50-alpha. Most mice homozygous for disruption for all 3 variants died within days after birth. Lymphocyte development and function were studied with the use of the RAG2-deficient blastocyst complementation system. Chimeric mice had reduced numbers of peripheral mature B cells and decreased serum immunoglobulin. The B cells that developed had diminished proliferative responses to antibody to immunoglobulin M, antibody to CD40, and lipopolysaccharide stimulation, as well as decreased survival after incubation with interleukin-4. In contrast, T-cell development and proliferation were normal. This phenotype was similar to defects observed in mice lacking the tyrosine kinase Btk and in patients with Bruton X-linked agammaglobulinemia (<a href="/entry/300300">300300</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9888855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Suzuki, H., Terauchi, Y., Fujiwara, M., Aizawa, S., Yazaki, Y., Kadowaki, T., Koyasu, S. <strong>Xid-like immunodeficiency in mice with disruption of the p85-alpha subunit of phosphoinositide 3-kinase.</strong> Science 283: 390-392, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9888854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9888854</a>] [<a href="https://doi.org/10.1126/science.283.5400.390" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9888854">Suzuki et al. (1999)</a> found that mice with a targeted gene disruption of p85-alpha had impaired B-cell development at the pro-B cell stage, reduced numbers of mature B cells and peritoneal CD5+ Ly-1 B cells, reduced B-cell proliferative responses, and no T cell-independent antibody production. These phenotypes were nearly identical to those of the mutant X-linked immunodeficiency (xid) mouse and of mice in whom the Btk gene has been disrupted. These results provided evidence that p85-alpha is functionally linked to the Btk pathway in antigen receptor-mediated signal transduction and is pivotal in B-cell development and functions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9888854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Terauchi, Y., Tsuji, Y., Satoh, S., Minoura, H., Murakami, K., Okuno, A., Inukai, K., Asano, T., Kaburagi, Y., Ueki, K., Nakajima, H., Hanafusa, T., and 18 others. <strong>Increased insulin sensitivity and hypoglycaemia in mice lacking the p85-alpha subunit of phosphoinositide 3-kinase.</strong> Nature Genet. 21: 230-235, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9988280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9988280</a>] [<a href="https://doi.org/10.1038/6023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9988280">Terauchi et al. (1999)</a> reported that Pik3r1 -/- mice show increased insulin sensitivity and hypoglycemia due to increased glucose transport in skeletal muscle and adipocytes. Insulin-stimulated PI3K activity associated with insulin receptor substrates was mediated by full-length p85-alpha in wildtype mice, but by the p50-alpha alternative splicing isoform of the same gene in Pik3r1 -/- mice. This isoform switch was associated with an increase in insulin-induced generation of phosphatidylinositol(3,4,5)triphosphate in Pik3r1 -/- adipocytes and facilitation of Glut4 (<a href="/entry/138190">138190</a>) translocation from the low density microsome fraction to the plasma membrane. This mechanism seemed to be responsible for the phenotype of the homozygous deficient mice, namely increased glucose transport and hypoglycemia. This work provided the first direct evidence that PI3K and its regulatory subunits have a role in glucose homeostasis in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9988280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Taniguchi, C. M., Tran, T. T., Kondo, T., Luo, J., Ueki, K., Cantley, L. C., Kahn, C. R. <strong>Phosphoinositide 3-kinase regulatory subunit p85-alpha suppresses insulin action via positive regulation of PTEN.</strong> Proc. Nat. Acad. Sci. 103: 12093-12097, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 113: E3588, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16880400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16880400</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16880400[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.0604628103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16880400">Taniguchi et al. (2006)</a> found that mice with a liver-specific deletion of Pik3r1 showed increased hepatic and peripheral insulin sensitivity. Pik3r1 ablation resulted in improved Akt activation, in part, because of decreased activity of the (3,4,5)-trisphosphate phosphatase Pten (<a href="/entry/601728">601728</a>). The authors concluded that Pik3r1 is a critical modulator of insulin sensitivity not only because of its effect on PI3K activation, but also as a regulator of PTEN activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16880400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Fukao, T., Yamada, T., Tanabe, M., Terauchi, Y., Ota, T., Takayama, T., Asano, T., Takeuchi, T., Kadowaki, T., Hata, J., Koyasu, S. <strong>Selective loss of gastrointestinal mast cells and impaired immunity in PI3K-deficient mice.</strong> Nature Immun. 3: 295-304, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11850627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11850627</a>] [<a href="https://doi.org/10.1038/ni768" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11850627">Fukao et al. (2002)</a> found that mice lacking p85-alpha were severely deficient in gastrointestinal and peritoneal mast cells, whereas dermal mast cells were present in the skin. The p85-alpha -/- mice were susceptible to acute septic peritonitis. However, they were also susceptible to systemic anaphylaxis, reflecting the absence of peritoneal mast cells but the presence of mast cells at other anatomic sites. Reconstitution of the mutant mice with bone marrow-derived mast cells (BMMCs) restored antibacterial immunity but not immunity to an intestinal nematode. Treatment of the BMMCs with Th2 lymphocyte-derived cytokines, i.e. IL4 (<a href="/entry/147780">147780</a>) and IL10 (<a href="/entry/124092">124092</a>), induced immunity to the parasitic worm, probably because mesenteric lymph node cells from the p85-alpha -/- mice produced reduced amounts of these cytokines. <a href="#16" class="mim-tip-reference" title="Fukao, T., Yamada, T., Tanabe, M., Terauchi, Y., Ota, T., Takayama, T., Asano, T., Takeuchi, T., Kadowaki, T., Hata, J., Koyasu, S. <strong>Selective loss of gastrointestinal mast cells and impaired immunity in PI3K-deficient mice.</strong> Nature Immun. 3: 295-304, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11850627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11850627</a>] [<a href="https://doi.org/10.1038/ni768" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11850627">Fukao et al. (2002)</a> concluded that PI3K plays an essential role in the development and induction of mast cells in normal and pathogenic immune responses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11850627" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Fukao, T., Tanabe, M., Terauchi, Y., Ota, T., Matsuda, S., Asano, T., Kadowaki, T., Takeuchi, T., Koyasu, S. <strong>PI3K-mediated negative feedback regulation of IL-12 production in DCs.</strong> Nature Immun. 3: 875-881, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12154357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12154357</a>] [<a href="https://doi.org/10.1038/ni825" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12154357">Fukao et al. (2002)</a> found that Pik3r1-deficient mice showed enhanced Th1-type responses after Leishmania major infection. Normal splenic dendritic cells (DCs) responded to IL12 (see <a href="/entry/161561">161561</a>) production-inducing stimuli with concomitant Pi3k activation. Splenic DCs from mutant mice or normal DCs treated with a Pi3k inhibitor showed increased IL12 production and reduced Th2 cytokine production. Because Pi3k inhibition and Pik3r1 deficiency resulted in enhanced IL12 production, <a href="#15" class="mim-tip-reference" title="Fukao, T., Tanabe, M., Terauchi, Y., Ota, T., Matsuda, S., Asano, T., Kadowaki, T., Takeuchi, T., Koyasu, S. <strong>PI3K-mediated negative feedback regulation of IL-12 production in DCs.</strong> Nature Immun. 3: 875-881, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12154357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12154357</a>] [<a href="https://doi.org/10.1038/ni825" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12154357">Fukao et al. (2002)</a> proposed that Pi3k is a negative regulator of IL12 production and that Pi3k inhibition may prevent potential immunopathologic effects of strong Th1 responses resulting from excessive IL12 production. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12154357" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Oak, J. S., Deane, J. A., Kharas, M. G., Luo, J., Lane, T. E., Cantley, L. C., Fruman, D. A. <strong>Sjogren's syndrome-like disease in mice with T cells lacking class 1A phosphoinositide-3-kinase.</strong> Proc. Nat. Acad. Sci. 103: 16882-16887, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 106: 10871 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17071741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17071741</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17071741[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.0607984103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17071741">Oak et al. (2006)</a> crossed mice with a floxed Pik3r1 allele and a null Pik3r2 allele with Lck (<a href="/entry/153390">153390</a>)-Cre transgenic mice to generate a strain in which class IA Pi3k expression and function were essentially abrogated in T cells beginning at the double-negative stage. Histopathologic analysis of these mice showed development of organ-specific autoimmunity resembling Sjogren syndrome (SS; <a href="/entry/270150">270150</a>). By 3 to 8 months of age, mutant mice developed corneal opacity and eye lesions due to irritation and constant scratching. Mutant mice showed marked lymphocytic infiltration of lacrimal glands and serum antinuclear and anti-Ssa (SSA1; <a href="/entry/109092">109092</a>) antibodies, but no kidney pathology. Cd4-positive T cells, which were the predominant infiltrating cells in lacrimal glands of mutant mice, exhibited aberrant differentiation in vitro. <a href="#24" class="mim-tip-reference" title="Oak, J. S., Deane, J. A., Kharas, M. G., Luo, J., Lane, T. E., Cantley, L. C., Fruman, D. A. <strong>Sjogren's syndrome-like disease in mice with T cells lacking class 1A phosphoinositide-3-kinase.</strong> Proc. Nat. Acad. Sci. 103: 16882-16887, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 106: 10871 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17071741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17071741</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17071741[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.0607984103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17071741">Oak et al. (2006)</a> concluded that impaired class IA PI3K signaling in T cells can lead to organ-specific autoimmunity, and they proposed that class IA Pi3k-deficient mice manifest the cardinal features of human primary SS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17071741" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=171833[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<p>In a 19-year-old girl with agammaglobulinemia-7 (AGM7; <a href="/entry/615214">615214</a>) and a severe defect in early B-cell development, <a href="#9" class="mim-tip-reference" title="Conley, M. E., Dobbs, A. K., Quintana, A. M., Bosompem, A., Wang, Y.-D., Coustan-Smith, E., Smith, A. M., Perez, E. E., Murray, P. J. <strong>Agammaglobulinemia and absent B lineage cells in a patient lacking the p85-alpha subunit of PI3K.</strong> J. Exp. Med. 209: 463-470, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22351933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22351933</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22351933[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.20112533" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22351933">Conley et al. (2012)</a> identified a homozygous G-to-A transition in exon 6 of the PIK3R1 gene, resulting in a trp298-to-ter (W298X) substitution in the Rac binding domain. The patient was from a consanguineous family of Chinese/Peruvian descent and had previously been reported by <a href="#10" class="mim-tip-reference" title="de la Morena, M., Haire, R. N., Ohta, Y., Nelson, R. P., Litman, R. T., Day, N. K., Good, R. A., Litman, G. W. <strong>Predominance of sterile immunoglobulin transcripts in a female phenotypically resembling Bruton's agammaglobulinemia.</strong> Europ. J. Immun. 25: 809-815, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7705412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7705412</a>] [<a href="https://doi.org/10.1002/eji.1830250327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7705412">de la Morena et al. (1995)</a> as having an autosomal recessive immunodeficiency reminiscent of Bruton agammaglobulinemia (<a href="/entry/300755">300755</a>). Each unaffected parent was heterozygous for the mutation, which was found by whole-exome sequencing and was not present in 1,000 in-house control alleles. The mutation resulted in absence of p85 expression, but normal p55 and p50 expression. The patient presented at 3.5 months of age with pneumonia and gastroenteritis. Laboratory studies showed panhypogammaglobulinemia, neutropenia, and decreased NK cells. T cells were essentially normal. As a teenager, she developed erythema nodosum, juvenile idiopathic arthritis, recurrent Campylobacter bacteremia, and inflammatory bowel disease, suggesting disordered cytokine production. The family history was positive for 2 older brothers and 2 maternal uncles who died of acute infections between 9 and 18 months of age. Flow cytometric analysis showed that the patient had near absence of B cells in peripheral blood, and bone marrow aspiration showed normal cellularity with almost complete absence of B lineage cells. However, there were normal percentages of very early CD34+,CD19- B-cell precursors. The patient had no p85 in T cells, neutrophils, or dendritic cells. There was decreased expression of p110 in patient immune cells, indicating that the N-terminal end of p85 contributes to binding and stabilization of p110. Overall, the findings suggested that mutations in the N-terminal region of p85 can result in failure of B-cell development at a very early stage, even earlier than in mouse models. Screening of the PIK3R1 gene in 55 additional patients with defects in B-cell development did not identify any other mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22351933+7705412" 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">rs397514046 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514046;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=rs397514046" 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=rs397514046" 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=RCV000054532 OR RCV000623355" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000054532, RCV000623355" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000054532...</a>
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<p>In a 7-year-old boy with SHORT syndrome (<a href="/entry/269880">269880</a>), <a href="#35" class="mim-tip-reference" title="Thauvin-Robinet, C., Auclair, M., Duplomb, L., Caron-Debarle, M., Avila, M., St-Onge, J., Le Merrer, M., Le Luyer, B., Heron, D., Mathieu-Dramard, M., Bitoun, P., Petit, J.-M., and 16 others. <strong>PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.</strong> Am. J. Hum. Genet. 93: 141-149, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23810378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23810378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23810378[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23810378">Thauvin-Robinet et al. (2013)</a> identified heterozygosity for a de novo 3-bp deletion (c.1615_1617delATT) at chr5:67,591,018 (GRCh37) in the PIK3R1 gene, resulting in deletion of ile539 in the inter-Src homology 2 (iSH2) domain. The mutation was not present in his unaffected parents and was not found in the NHLBI Exome Variant Server, dbSNP (build 137), or 1000 Genomes Project databases. Functional studies on patient fibroblasts revealed a 70 to 90% reduction in the effect of insulin on AKT (see <a href="/entry/164730">164730</a>) activation, glycogen synthesis, and glucose uptake, indicating severe insulin resistance for both proximal and distal PI3K-dependent signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23810378" 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">rs397514047 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514047;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=rs397514047" 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=rs397514047" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 7-year-old boy with SHORT syndrome (<a href="/entry/269880">269880</a>), <a href="#35" class="mim-tip-reference" title="Thauvin-Robinet, C., Auclair, M., Duplomb, L., Caron-Debarle, M., Avila, M., St-Onge, J., Le Merrer, M., Le Luyer, B., Heron, D., Mathieu-Dramard, M., Bitoun, P., Petit, J.-M., and 16 others. <strong>PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.</strong> Am. J. Hum. Genet. 93: 141-149, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23810378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23810378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23810378[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23810378">Thauvin-Robinet et al. (2013)</a> identified heterozygosity for a de novo c.1465G-A transition at chr5:67,590,403 (GRCh37) in the PIK3R1 gene, resulting in a glu489-to-lys (E489K) substitution at a highly conserved residue in the inter-Src homology 2 (iSH2) domain. The mutation was not present in his unaffected parents and was not found in the NHLBI Exome Variant Server, dbSNP (build 137), or 1000 Genomes Project databases. Functional studies on patient fibroblasts revealed a 70 to 90% reduction in the effect of insulin on AKT (see <a href="/entry/164730">164730</a>) activation, glycogen synthesis, and glucose uptake, indicating severe insulin resistance for both proximal and distal PI3K-dependent signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23810378" 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">rs397515453 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515453;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=rs397515453" 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=rs397515453" 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=RCV000054534 OR RCV000414540 OR RCV000515192 OR RCV001197921 OR RCV001265992" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000054534, RCV000414540, RCV000515192, RCV001197921, RCV001265992" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000054534...</a>
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<p>In 5 patients from 4 families with SHORT syndrome (<a href="/entry/269880">269880</a>), including a patient previously reported by <a href="#4" class="mim-tip-reference" title="Bonnel, S., Dureau, P., LeMerrer, M., Dufier, J. L. <strong>SHORT syndrome: a case with high hyperopia and astigmatism.</strong> Ophthal. Genet. 21: 235-238, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11135494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11135494</a>]" pmid="11135494">Bonnel et al. (2000)</a>, <a href="#35" class="mim-tip-reference" title="Thauvin-Robinet, C., Auclair, M., Duplomb, L., Caron-Debarle, M., Avila, M., St-Onge, J., Le Merrer, M., Le Luyer, B., Heron, D., Mathieu-Dramard, M., Bitoun, P., Petit, J.-M., and 16 others. <strong>PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.</strong> Am. J. Hum. Genet. 93: 141-149, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23810378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23810378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23810378[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23810378">Thauvin-Robinet et al. (2013)</a> identified heterozygosity for a c.1945C-T transition at chr5:67,592,129 (GRCh37) in the PIK3R1 gene, resulting in an arg649-to-trp (R649W) substitution at a highly conserved residue in the cSH2 domain. In the 1 family for which parental DNA was available, the mutation was shown to be de novo. <a href="#35" class="mim-tip-reference" title="Thauvin-Robinet, C., Auclair, M., Duplomb, L., Caron-Debarle, M., Avila, M., St-Onge, J., Le Merrer, M., Le Luyer, B., Heron, D., Mathieu-Dramard, M., Bitoun, P., Petit, J.-M., and 16 others. <strong>PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.</strong> Am. J. Hum. Genet. 93: 141-149, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23810378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23810378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23810378[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23810378">Thauvin-Robinet et al. (2013)</a> noted that the c.1945C-T mutation occurred within the context of a CpG dinucleotide, which might explain its recurrence. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11135494+23810378" 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 affected members of a 3-generation Norwegian family with SHORT syndrome, originally described by <a href="#1" class="mim-tip-reference" title="Aarskog, D., Ose, L., Pande, H., Eide, N. <strong>Autosomal dominant partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes.</strong> Am. J. Med. Genet. 15: 29-38, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6407320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6407320</a>] [<a href="https://doi.org/10.1002/ajmg.1320150104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6407320">Aarskog et al. (1983)</a>, and a German mother and son with SHORT syndrome, originally reported by <a href="#19" class="mim-tip-reference" title="Koenig, R., Brendel, L., Fuchs, S. <strong>SHORT syndrome.</strong> Clin. Dysmorph. 12: 45-49, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12514365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12514365</a>] [<a href="https://doi.org/10.1097/00019605-200301000-00008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12514365">Koenig et al. (2003)</a>, <a href="#8" class="mim-tip-reference" title="Chudasama, K. K., Winnay, J., Johansson, S., Claudi, T., Konig, R., Haldorsen, I., Johansson, B., Woo, J. R., Aarskog, D., Sagen, J. V., Kahn, C. R., Molven, A., Njolstad, P. R. <strong>SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling.</strong> Am. J. Hum. Genet. 93: 150-157, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23810379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23810379</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23810379[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23810379">Chudasama et al. (2013)</a> identified heterozygosity for the R649W missense mutation in the PIK3R1 gene. The mutation was not found in 340 Norwegian controls. Haplotype analysis showed that the mutations resided on different backgrounds in the 2 families, indicating that they stemmed from 2 independent mutational events. Analysis of patient fibroblasts and reconstituted Pik3r1-knockout preadipocytes demonstrated impaired interaction between p85-alpha and IRS1 (<a href="/entry/147545">147545</a>) and reduced AKT (see <a href="/entry/164730">164730</a>)-mediated insulin signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12514365+6407320+23810379" 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 mother and 2 sons from an English family with SHORT syndrome, originally reported by <a href="#3" class="mim-tip-reference" title="Bankier, A., Keith, C. G., Temple, I. K. <strong>Absent iris stroma, narrow body build and small facial bones: a new association or variant of SHORT syndrome?</strong> Clin. Dysmorph. 4: 304-312, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8574420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8574420</a>] [<a href="https://doi.org/10.1097/00019605-199510000-00005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8574420">Bankier et al. (1995)</a> and restudied by <a href="#28" class="mim-tip-reference" title="Reardon, W., Temple, I. K. <strong>Nephrocalcinosis and disordered calcium metabolism in two children with SHORT syndrome.</strong> Am. J. Med. Genet. 146A: 1296-1298, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18384141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18384141</a>] [<a href="https://doi.org/10.1002/ajmg.a.32250" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18384141">Reardon and Temple (2008)</a>, and in an unrelated male patient, <a href="#12" class="mim-tip-reference" title="Dyment, D. A., Smith, A. C., Alcantara, D., Schwartzentruber, J. A., Basel-Vanagaite, L., Curry, C. J., Temple, I. K., Reardon, W., Mansour, S., Haq, M. R., Gilbert, R., Lehmann, O. J., Vanstone, M. R., Beaulieu, C. L., FORGE Canada Consortium, Majewski, J., Bulman, D. E., O'Driscoll, M., Boycott, K. M., Innes, A. M. <strong>Mutations in PIK3R1 cause SHORT syndrome.</strong> Am. J. Hum. Genet. 93: 158-166, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23810382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23810382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23810382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.06.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23810382">Dyment et al. (2013)</a> identified heterozygosity for the R649W mutation in the PIK3R1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18384141+23810382+8574420" 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 60-year-old woman with severe insulin resistance, generalized lipoatrophy, and facial dysmorphism consistent with SHORT syndrome (<a href="/entry/269880">269880</a>), <a href="#35" class="mim-tip-reference" title="Thauvin-Robinet, C., Auclair, M., Duplomb, L., Caron-Debarle, M., Avila, M., St-Onge, J., Le Merrer, M., Le Luyer, B., Heron, D., Mathieu-Dramard, M., Bitoun, P., Petit, J.-M., and 16 others. <strong>PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.</strong> Am. J. Hum. Genet. 93: 141-149, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23810378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23810378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23810378[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23810378">Thauvin-Robinet et al. (2013)</a> identified heterozygosity for a 1-bp duplication (c.1943dupT) in the PIK3R1 gene, causing a frameshift predicted to result in a premature termination codon (Arg649ProfsTer5). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23810378" 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 2-year-old girl with SHORT syndrome (<a href="/entry/269880">269880</a>), <a href="#12" class="mim-tip-reference" title="Dyment, D. A., Smith, A. C., Alcantara, D., Schwartzentruber, J. A., Basel-Vanagaite, L., Curry, C. J., Temple, I. K., Reardon, W., Mansour, S., Haq, M. R., Gilbert, R., Lehmann, O. J., Vanstone, M. R., Beaulieu, C. L., FORGE Canada Consortium, Majewski, J., Bulman, D. E., O'Driscoll, M., Boycott, K. M., Innes, A. M. <strong>Mutations in PIK3R1 cause SHORT syndrome.</strong> Am. J. Hum. Genet. 93: 158-166, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23810382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23810382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23810382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.06.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23810382">Dyment et al. (2013)</a> identified heterozygosity for a de novo 1-bp insertion (c.1906_1907insC) in exon 14 of the PIK3R1 gene, causing a frameshift predicted to generate a premature termination codon (Asn636ThrfsTer18). The mutation was not found in her unaffected parents. Functional analysis of patient lymphoblastoid cells showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT (see <a href="/entry/164730">164730</a>)-mTOR (<a href="/entry/601231">601231</a>) pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23810382" 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">rs587777709 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777709;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=rs587777709" 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=rs587777709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with immunodeficiency-36 with lymphoproliferation (IMD36; <a href="/entry/616005">616005</a>), <a href="#11" class="mim-tip-reference" title="Deau, M.-C., Heurtier, L., Frange, P., Suarez, F., Bole-Feysot, C., Nitschke, P., Cavazzana, M., Picard, C., Durandy, A., Fischer, A., Kracker, S. <strong>A human immunodeficiency caused by mutations in the PIK3R1 gene.</strong> J. Clin. Invest. 124: 3923-3928, 2014. Note: Erratum: J. Clin. Invest. 125: 1764 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25133428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25133428</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25133428[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI75746" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25133428">Deau et al. (2014)</a> identified a de novo heterozygous G-to-T transversion in intron 10 of the PIK3R1 gene, resulting in an in-frame deletion of exon 10 and removal of a peptide sequence (amino acid residues 434-475) that is part of an alpha-helix involved in p110 binding. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database or in an in-house control database. The same splice site mutation, resulting from a different nucleotide change (<a href="#0008">171833.0008</a>), was found in 3 additional patients with a similar disorder. Both mutations resulted in a loss of p85-mediated inhibition and caused increased phosphorylation of downstream signaling pathways, consistent with a gain of function. Immunologic studies showed a defect in both B- and T-cell differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25133428" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Lucas, C. L., Zhang, Y., Venida, A., Wang, Y., Hughes, J., McElwee, J., Butrick, M., Matthews, H., Price, S., Biancalana, M., Wang, X., Richards, M., Pozos, T., Barlan, I., Ozen, A., Rao, V. K., Su, H. C., Lenardo, M. J. <strong>Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.</strong> J. Exp. Med. 211: 2537-2547, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25488983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25488983</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25488983[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.20141759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25488983">Lucas et al. (2014)</a> designated the c.1425+1 splice site as occurring in intron 11 of the PIK3R1 gene (c.1425+1G-T, NM_181523.2). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25488983" 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 19-month-old Italian girl with recurrent respiratory infections and poor growth, who had hypogammaglobulinemia with elevated serum IgM levels and lymphoproliferation, <a href="#20" class="mim-tip-reference" title="Lougaris, V., Faletra, F., Lanzi, G., Vozzi, D., Marcuzzi, A., Valencic, E., Piscianz, E., Bianco, A., Girardelli, M., Baronio, M., Loganes, C., Fasth, A., Salvini, F., Trizzino, A., Moratto, D., Facchetti, F., Giliani, S., Plebani, A., Tommasini, A. <strong>Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype. (Letter)</strong> Clin. Immun. 159: 33-36, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25939554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25939554</a>] [<a href="https://doi.org/10.1016/j.clim.2015.04.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25939554">Lougaris et al. (2015)</a> identified heterozygosity for the c.1425+1G-T splice site mutation in the PIK3R1 gene. The mutation occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25939554" 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">rs587777709 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777709;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=rs587777709" 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=rs587777709" 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=RCV000144066 OR RCV000508456 OR RCV000623166 OR RCV000800719 OR RCV003156075" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144066, RCV000508456, RCV000623166, RCV000800719, RCV003156075" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144066...</a>
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<p>In 3 patients from 2 unrelated families with immunodeficiency-36 with lymphoproliferation (IMD36; <a href="/entry/616005">616005</a>), <a href="#11" class="mim-tip-reference" title="Deau, M.-C., Heurtier, L., Frange, P., Suarez, F., Bole-Feysot, C., Nitschke, P., Cavazzana, M., Picard, C., Durandy, A., Fischer, A., Kracker, S. <strong>A human immunodeficiency caused by mutations in the PIK3R1 gene.</strong> J. Clin. Invest. 124: 3923-3928, 2014. Note: Erratum: J. Clin. Invest. 125: 1764 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25133428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25133428</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25133428[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI75746" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25133428">Deau et al. (2014)</a> identified a heterozygous G-to-C transversion in intron 10 of the PIK3R1 gene, resulting in an in-frame deletion of exon 10 and removal of a peptide sequence (amino acids 434-475) that is part of an alpha-helix involved in p110 binding. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database or in an in-house control database. In 1 family, a mother and child were affected. The same splice site mutation, resulting from a different nucleotide change (<a href="#0007">171833.0007</a>), was found in another patient with a similar disorder. Both mutations resulted in a loss of p85-mediated inhibition and caused increased phosphorylation of downstream signaling pathways, consistent with a gain of function. Immunologic studies showed a defect in both B- and T-cell differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25133428" 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 32-year-old Turkish woman and a Caucasian American mother and son with immunodeficiency, <a href="#21" class="mim-tip-reference" title="Lucas, C. L., Zhang, Y., Venida, A., Wang, Y., Hughes, J., McElwee, J., Butrick, M., Matthews, H., Price, S., Biancalana, M., Wang, X., Richards, M., Pozos, T., Barlan, I., Ozen, A., Rao, V. K., Su, H. C., Lenardo, M. J. <strong>Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.</strong> J. Exp. Med. 211: 2537-2547, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25488983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25488983</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25488983[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.20141759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25488983">Lucas et al. (2014)</a> identified heterozygosity for the c.1425+1G-C mutation, which they designated as occurring in intron 11 of the PIK3R1 gene (c.1425+1G-C, NM_181523.2). Sequencing of patient cDNA demonstrated that the mutation causes skipping of exon 11, resulting in an in-frame deletion of residues 434 to 475 of the p85-alpha regulatory subunit. Analysis of PI3K signaling in patient T-cell blasts showed increased phosphorylation of AKT (<a href="/entry/164730">164730</a>) and downstream targets compared to controls, indicating constitutive hyperactivation of PI3K and AKT. The mutant p85-alpha protein was detected at low levels in patient cells, and overexpression of the mutant in control T cells demonstrated a dominant gain-of-function effect on PI3K signaling. In addition, the authors showed that this hyperactivation is due to qualitatively and quantitatively different binding to, and impaired inhibition of, the p110-delta catalytic subunit (PIK3CD; <a href="/entry/602839">602839</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25488983" 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 5-year-old Chinese boy with immunodeficiency-36 with lymphoproliferation (IMD36; <a href="/entry/616005">616005</a>), who also exhibited lymphadenopathy, hepatomegaly, and severe juvenile rheumatoid arthritis, <a href="#21" class="mim-tip-reference" title="Lucas, C. L., Zhang, Y., Venida, A., Wang, Y., Hughes, J., McElwee, J., Butrick, M., Matthews, H., Price, S., Biancalana, M., Wang, X., Richards, M., Pozos, T., Barlan, I., Ozen, A., Rao, V. K., Su, H. C., Lenardo, M. J. <strong>Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K.</strong> J. Exp. Med. 211: 2537-2547, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25488983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25488983</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25488983[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.20141759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25488983">Lucas et al. (2014)</a> identified heterozygosity for a c.1425+1G-A mutation (c.1425+1G-A, NM_181523.2) in intron 11 of the PIK3R1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25488983" 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 9-month-old Albanian girl, a 3-year-old Italian boy, and a 3.5-year-old Swedish girl with recurrent respiratory infections and poor growth, who had hypogammaglobulinemia with elevated serum IgM levels and lymphoproliferation, <a href="#20" class="mim-tip-reference" title="Lougaris, V., Faletra, F., Lanzi, G., Vozzi, D., Marcuzzi, A., Valencic, E., Piscianz, E., Bianco, A., Girardelli, M., Baronio, M., Loganes, C., Fasth, A., Salvini, F., Trizzino, A., Moratto, D., Facchetti, F., Giliani, S., Plebani, A., Tommasini, A. <strong>Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype. (Letter)</strong> Clin. Immun. 159: 33-36, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25939554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25939554</a>] [<a href="https://doi.org/10.1016/j.clim.2015.04.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25939554">Lougaris et al. (2015)</a> identified heterozygosity for the c.1425+1G-A mutation in the PIK3R1 gene. The mutation was shown to have occurred de novo in 2 of the patients; the genotype of the Swedish parents was unknown. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25939554" 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 4 unrelated children (patients 1-4) with immunodeficiency and elevated IgM levels, lymphadenopathy, and short stature, <a href="#27" class="mim-tip-reference" title="Petrovski, S., Parrott, R. E., Roberts, J. L., Huang, H., Yang, J., Gorentla, B., Mousallem, T., Wang, E., Armstrong, M., McHale, D., MacIver, N. J., Goldstein, D. B., Zhong, X.-P., Buckley, R. H. <strong>Dominant splice site mutations in PIK3R1 cause hyper IgM syndrome, lymphadenopathy and short stature.</strong> J. Clin. Immun. 36: 462-471, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27076228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27076228</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27076228[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/10.1007/s10875-016-0281-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27076228">Petrovski et al. (2016)</a> identified heterozygosity for the c.1425+1G-A mutation in PIK3R1. The mutation was confirmed to have arisen de novo in 3 of the patients; it was not found in the fourth child's unaffected mother, but DNA was unavailable from the father. Analysis of PCR products from patient 1 and his parents demonstrated that the mutation causes skipping of exon 11, with direct exon 10 to exon 12 splicing. Results of functional analysis using patient cells were consistent with constitutive activation of the PI3K-mTOR (<a href="/entry/601231">601231</a>) signaling. Patient 4, a 5-year-old Caucasian girl, also exhibited features of SHORT syndrome (<a href="/entry/269880">269880</a>); the authors noted that no results of immune studies had been reported for SHORT syndrome patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27076228" 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">rs1554051075 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554051075;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=rs1554051075" 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=rs1554051075" 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=RCV000515774 OR RCV002527446" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000515774, RCV002527446" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000515774...</a>
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<p>In 2 patients with immunodeficiency-36 with lymphoproliferation (IMD36; <a href="/entry/616005">616005</a>), <a href="#13" class="mim-tip-reference" title="Elkaim, E., Neven, B., Bruneau, J., Mitsui-Sekinaka, K., Stanislas, A., Heurtier, L., Lucas, C. L., Matthews, H., Deau, M.-C., Sharapova, S., Curtis, J., Reichenbach, J., and 31 others. <strong>Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study.</strong> J. Allergy Clin. Immun. 138: 210-218, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27221134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27221134</a>] [<a href="https://doi.org/10.1016/j.jaci.2016.03.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27221134">Elkaim et al. (2016)</a> identified heterozygosity for a c.1425+2T-A transversion (c.1425+2T-A, NM_181523.2) in intron 11 of the PIK3R1 gene. Analysis of patient mRNA demonstrated skipping of exon 11 (coding exon 10), encoding amino acids 434 to 475 of p85-alpha. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27221134" 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">rs1554051075 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554051075;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=rs1554051075" 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=rs1554051075" 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=RCV000515763 OR RCV001815343" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000515763, RCV001815343" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000515763...</a>
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<p>In a patient (P8) with immunodeficiency-36 with lymphoproliferation (IMD36; <a href="/entry/616005">616005</a>), <a href="#13" class="mim-tip-reference" title="Elkaim, E., Neven, B., Bruneau, J., Mitsui-Sekinaka, K., Stanislas, A., Heurtier, L., Lucas, C. L., Matthews, H., Deau, M.-C., Sharapova, S., Curtis, J., Reichenbach, J., and 31 others. <strong>Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study.</strong> J. Allergy Clin. Immun. 138: 210-218, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27221134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27221134</a>] [<a href="https://doi.org/10.1016/j.jaci.2016.03.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27221134">Elkaim et al. (2016)</a> identified heterozygosity for a c.1425+2T-G transversion (c.1425+2T-G, NM_181523.2) in intron 11 of the PIK3R1 gene. Analysis of patient mRNA demonstrated skipping of exon 11 (coding exon 10), encoding amino acids 434 to 475 of p85-alpha. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27221134" 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">rs1554051067 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554051067;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=rs1554051067" 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=rs1554051067" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient (P10) with immunodeficiency-36 with lymphoproliferation (IMD36; <a href="/entry/616005">616005</a>), <a href="#13" class="mim-tip-reference" title="Elkaim, E., Neven, B., Bruneau, J., Mitsui-Sekinaka, K., Stanislas, A., Heurtier, L., Lucas, C. L., Matthews, H., Deau, M.-C., Sharapova, S., Curtis, J., Reichenbach, J., and 31 others. <strong>Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study.</strong> J. Allergy Clin. Immun. 138: 210-218, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27221134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27221134</a>] [<a href="https://doi.org/10.1016/j.jaci.2016.03.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27221134">Elkaim et al. (2016)</a> identified heterozygosity for a 2-bp deletion (c.1425+2delTG, NM_181523.2) in intron 11 of the PIK3R1 gene. Analysis of patient mRNA demonstrated skipping of exon 11 (coding exon 10), encoding amino acids 434 to 475 of p85-alpha. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27221134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 IMMUNODEFICIENCY 36 WITH LYMPHOPROLIFERATION</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">rs1554051033 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554051033;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=rs1554051033" 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=rs1554051033" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient (P19) with immunodeficiency-36 with lymphoproliferation (IMD36; <a href="/entry/616005">616005</a>), <a href="#13" class="mim-tip-reference" title="Elkaim, E., Neven, B., Bruneau, J., Mitsui-Sekinaka, K., Stanislas, A., Heurtier, L., Lucas, C. L., Matthews, H., Deau, M.-C., Sharapova, S., Curtis, J., Reichenbach, J., and 31 others. <strong>Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study.</strong> J. Allergy Clin. Immun. 138: 210-218, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27221134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27221134</a>] [<a href="https://doi.org/10.1016/j.jaci.2016.03.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27221134">Elkaim et al. (2016)</a> identified heterozygosity for a c.1300-1G-C transversion (c.1300-1G-C, NM_181523.2) in intron 10 of the PIK3R1 gene. Analysis of patient mRNA demonstrated skipping of exon 11 (coding exon 10), encoding amino acids 434 to 475 of p85-alpha. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27221134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1016/j.ajhg.2013.06.005" target="_blank">Full Text</a>]
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Elkaim, E., Neven, B., Bruneau, J., Mitsui-Sekinaka, K., Stanislas, A., Heurtier, L., Lucas, C. L., Matthews, H., Deau, M.-C., Sharapova, S., Curtis, J., Reichenbach, J., and 31 others.
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[<a href="https://doi.org/10.1016/j.jaci.2016.03.022" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.283.5400.393" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ni825" target="_blank">Full Text</a>]
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<li>
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<a id="30" class="mim-anchor"></a>
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<a id="Simoncini2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Simoncini, T., Hafezi-Moghadam, A., Brazil, D. P., Ley, K., Chin, W. W., Liao, J. K.
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<strong>Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase.</strong>
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Nature 407: 538-541, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11029009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11029009</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11029009[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=11029009" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/35035131" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="31" class="mim-anchor"></a>
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<a id="Skolnik1991" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Skolnik, E. Y., Margolis, B., Mohammadi, M., Lowenstein, E., Fischer, R., Drepps, A., Ullrich, A., Schlessinger, J.
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|
<strong>Cloning of PI3-kinase associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases.</strong>
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Cell 65: 83-90, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1849461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1849461</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1849461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0092-8674(91)90410-z" 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="32" class="mim-anchor"></a>
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<a id="Suzuki1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Suzuki, H., Terauchi, Y., Fujiwara, M., Aizawa, S., Yazaki, Y., Kadowaki, T., Koyasu, S.
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<strong>Xid-like immunodeficiency in mice with disruption of the p85-alpha subunit of phosphoinositide 3-kinase.</strong>
|
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Science 283: 390-392, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9888854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9888854</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9888854" 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.283.5400.390" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="33" class="mim-anchor"></a>
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<a id="Taniguchi2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Taniguchi, C. M., Tran, T. T., Kondo, T., Luo, J., Ueki, K., Cantley, L. C., Kahn, C. R.
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<strong>Phosphoinositide 3-kinase regulatory subunit p85-alpha suppresses insulin action via positive regulation of PTEN.</strong>
|
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Proc. Nat. Acad. Sci. 103: 12093-12097, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 113: E3588, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16880400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16880400</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16880400[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=16880400" 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.0604628103" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="34" class="mim-anchor"></a>
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<a id="Terauchi1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Terauchi, Y., Tsuji, Y., Satoh, S., Minoura, H., Murakami, K., Okuno, A., Inukai, K., Asano, T., Kaburagi, Y., Ueki, K., Nakajima, H., Hanafusa, T., and 18 others.
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<strong>Increased insulin sensitivity and hypoglycaemia in mice lacking the p85-alpha subunit of phosphoinositide 3-kinase.</strong>
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Nature Genet. 21: 230-235, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9988280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9988280</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9988280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/6023" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="35" class="mim-anchor"></a>
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<a id="Thauvin-Robinet2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thauvin-Robinet, C., Auclair, M., Duplomb, L., Caron-Debarle, M., Avila, M., St-Onge, J., Le Merrer, M., Le Luyer, B., Heron, D., Mathieu-Dramard, M., Bitoun, P., Petit, J.-M., and 16 others.
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<strong>PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.</strong>
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Am. J. Hum. Genet. 93: 141-149, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23810378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23810378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23810378[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=23810378" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2013.05.019" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="36" class="mim-anchor"></a>
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<a id="Volinia1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Volinia, S., Patracchini, P., Otsu, M., Hiles, I., Gout, I., Calzolari, E., Bernardi, F., Rooke, L., Waterfield, M. D.
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<strong>Chromosomal localization of human p85-alpha, a subunit of phosphatidylinositol 3-kinase, and its homologue p85-beta.</strong>
|
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Oncogene 7: 789-793, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1314371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1314371</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1314371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</li>
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<li>
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<a id="37" class="mim-anchor"></a>
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<a id="Winnay2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Winnay, J. N., Boucher, J., Mori, M. A., Ueki, K., Kahn, C. R.
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<strong>A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box-binding protein-1 to modulate the unfolded protein response.</strong>
|
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Nature Med. 16: 438-445, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20348923/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20348923</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20348923[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=20348923" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nm.2121" target="_blank">Full Text</a>]
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</p>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 06/28/2019
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 12/04/2017<br>Cassandra L. Kniffin - updated : 9/15/2014<br>Marla J. F. O'Neill - updated : 8/23/2013<br>Cassandra L. Kniffin - updated : 4/30/2013<br>Patricia A. Hartz - updated : 6/7/2010<br>George E. Tiller - updated : 2/23/2010<br>Ada Hamosh - updated : 11/26/2008<br>Ada Hamosh - updated : 7/31/2007<br>Paul J. Converse - updated : 1/16/2007<br>Patricia A. Hartz - updated : 9/15/2006<br>Patricia A. Hartz - updated : 12/17/2002<br>Paul J. Converse - updated : 9/5/2002<br>Paul J. Converse - updated : 4/29/2002<br>Victor A. McKusick - updated : 3/5/2002<br>Ada Hamosh - updated : 10/18/2000<br>Victor A. McKusick - updated : 3/3/1999<br>Victor A. McKusick - updated : 1/14/1999
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</span>
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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="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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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 7/1/1992
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 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="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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ckniffin : 03/14/2023<br>mgross : 07/01/2019<br>mgross : 06/28/2019<br>carol : 12/05/2017<br>carol : 12/04/2017<br>carol : 08/24/2017<br>carol : 03/28/2017<br>carol : 08/10/2016<br>carol : 10/01/2014<br>carol : 9/17/2014<br>ckniffin : 9/15/2014<br>carol : 11/12/2013<br>alopez : 8/23/2013<br>carol : 5/1/2013<br>ckniffin : 5/1/2013<br>ckniffin : 4/30/2013<br>terry : 6/6/2012<br>mgross : 6/10/2010<br>mgross : 6/10/2010<br>terry : 6/7/2010<br>wwang : 3/2/2010<br>terry : 2/23/2010<br>alopez : 12/5/2008<br>alopez : 12/5/2008<br>terry : 11/26/2008<br>mgross : 8/13/2007<br>alopez : 8/3/2007<br>alopez : 8/3/2007<br>terry : 7/31/2007<br>mgross : 1/16/2007<br>wwang : 9/22/2006<br>terry : 9/15/2006<br>wwang : 5/20/2005<br>mgross : 1/6/2003<br>terry : 12/17/2002<br>alopez : 9/20/2002<br>mgross : 9/5/2002<br>mgross : 4/29/2002<br>mgross : 3/11/2002<br>terry : 3/5/2002<br>cwells : 10/24/2001<br>cwells : 10/24/2001<br>terry : 10/23/2001<br>carol : 9/13/2001<br>alopez : 10/18/2000<br>carol : 3/9/1999<br>terry : 3/3/1999<br>alopez : 1/14/1999<br>alopez : 1/14/1999<br>joanna : 1/14/1999<br>alopez : 10/19/1998<br>psherman : 6/29/1998<br>alopez : 6/2/1997<br>jamie : 11/8/1996<br>carol : 1/9/1995<br>terry : 12/20/1994<br>carol : 10/15/1992<br>carol : 7/1/1992
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</span>
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</div>
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</div>
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</div>
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</div>
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</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">
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<strong>*</strong> 171833
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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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PHOSPHATIDYLINOSITOL 3-KINASE, REGULATORY SUBUNIT 1; PIK3R1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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PHOSPHATIDYLINOSITOL 3-KINASE-ASSOCIATED p85-ALPHA; GRB1<br />
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PHOSPHATIDYLINOSITOL 3-KINASE, REGULATORY SUBUNIT, 85-KD, ALPHA<br />
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p85-ALPHA
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: PIK3R1</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 5q13.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 5:68,215,756-68,301,821 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
|
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Inheritance
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</th>
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<th>
|
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Phenotype <br /> mapping key
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</th>
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</tr>
|
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="3">
|
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<span class="mim-font">
|
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5q13.1
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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?Agammaglobulinemia 7, autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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615214
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Immunodeficiency 36
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</span>
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</td>
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<td>
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<span class="mim-font">
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616005
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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SHORT syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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269880
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates the inositol ring of phosphatidylinositol and related compounds at the 3-prime position. The products of these reactions are thought to serve as second messengers in growth signaling pathways. The kinase itself is made up of a catalytic subunit of molecular mass 110 kD (p110; e.g., PIK3CA, 171834) and a regulatory subunit, often of molecular mass 85 kD (p85), such as PIK3R1 (summary by Hoyle et al., 1994). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Otsu et al. (1991) showed that the bovine PI3K p85 subunit consists of 2 closely related proteins, p85-alpha and p85-beta (PIK3R2; 603157). They cloned cDNAs encoding both p85 subunits, each of which is a 724-amino acid polypeptide. The 2 subunits shared 62% amino acid sequence identity across their entire length. Both sequences contained an N-terminal SH3 region, 2 SH2 regions, and a region of homology to the C-terminal region of BCR (151410). Functional expression studies showed that both p85 subunits lacked PI3-kinase activity, but both bound to tyrosine kinase receptors. Volinia et al. (1992) stated that human p85-alpha contains all the peptide sequence found in bovine p85-alpha. </p><p>Skolnik et al. (1991) developed a novel method for expression cloning of receptor tyrosine kinase target proteins (called CORT for 'cloning of receptor targets') and illustrated the method by cloning cDNA for GRB1, the gene encoding phosphatidylinositol 3-kinase-associated p85-alpha. </p><p>The PIK3R1 gene encodes 3 regulatory isoforms of PI3K: p85, p55, and p50. The 9 3-prime exons are shared by all 3 isoforms with 2 distinct promoters, and 2 exon 1 sequences upstream of these 9 exons control the production of p55 and p50 (summary by Conley et al., 2012). </p><p>Conley et al. (2012) found variable expression of the 3 regulatory isoforms in hematopoietic cells: normal T cells expressed almost equal amounts of p85 and p50, and activated T cells also contained trace amounts of p55. In contrast, normal B cells contained p85, but no detectable p50 or p55; EBV-transformed B cells expressed low levels of p50 and p55. NK cells and neutrophils contained p85 and low levels of p50. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Skolnik et al. (1991) showed that the product of the GRB1 gene associates with activated growth factor receptors. p85-alpha modulates the interaction between PI3 kinase and platelet-derived growth factor receptor. </p><p>Simoncini et al. (2000) showed that the estrogen receptor isoform ER-alpha (133430) binds in a ligand-dependent manner to the p85-alpha regulatory subunit of PI3K. Stimulation with estrogen increases ER-alpha-associated PI3K activity, leading to the activation of protein kinase B/AKT (164730) and endothelial nitric oxide synthase (eNOS; 163729). Recruitment and activation of PI3K by ligand-bound ER-alpha are independent of gene transcription, do not involve phosphotyrosine adaptor molecules or src-homology domains of p85-alpha, and extend to other steroid hormone receptors. Mice treated with estrogen showed increased eNOS activity and decreased vascular leukocyte accumulation after ischemia and reperfusion injury. This vascular protective effect of estrogen was abolished in the presence of PI3K or eNOS inhibitors. Simoncini et al. (2000) concluded that their findings defined a physiologically important nonnuclear estrogen-signaling pathway involving the direct interaction of ER-alpha with PI3K. </p><p>Niswender et al. (2001) demonstrated that systemic administration of leptin (164160) in rat activates the enzyme phosphatidylinositol-3-hydroxykinase in the hypothalamus and that intracerebroventricular infusion of inhibitors of this enzyme prevents leptin-induced anorexia. They concluded that phosphatidylinositol-3-hydroxykinase is a crucial enzyme in the signal transduction pathway that links hypothalamic leptin to reduced food intake. </p><p>He et al. (2002) determined that the hepatitis C virus nonstructural 5A (NS5A) protein interacts directly with GRB2 (108355) and with the p85 subunit of PI3K following stimulation with epidermal growth factor (EGF; 131530). The in vivo association of NS5A with p85 PI3K increased tyrosine phosphorylation of p85 PI3K. Downstream effects of the EGF-induced interaction included tyrosine phosphorylation of AKT and serine phosphorylation of BAD (603167). Both of these events would tend to inhibit apoptosis and were consistent with the antiapoptotic properties of NS5A. </p><p>Ectopic activation of fibroblast growth factor receptor-3 (FGFR3; 134934) is associated with several cancers, including multiple myeloma (254500). Salazar et al. (2009) identified the PI3K regulatory subunit PIK3R1 as a novel interactor of FGFR3 by yeast 2-hybrid screen and confirmed an interaction between FGFR3 and PIK3R1 and PIK3R2 in mammalian cells. The interaction of FGFR3 with PIK3R1 was dependent upon receptor activation. In contrast to the Gab1 (604439)-mediated association of FGFRs with PIK3R1, the FGFR3-PIK3R1 interaction required FGFR3 tyr760, previously identified as a PLC-gamma (PLCG1; 172420)-binding site. Interaction of PIK3R1 with FGFR3 did not require PLC-gamma, suggesting that PIK3R1 interaction was direct and independent of PLC-gamma binding. FGFR3 and PIK3R1/PIK3R2 proteins also interacted in multiple myeloma cell lines, which consistently express PIK3R1 p85 isoforms but not p50 or p55 isoforms, or PIK3R3 (606076). siRNA knockdown of PIK3R2 in multiple myeloma cells caused an increased ERK response to FGF2 stimulation. Salazar et al. (2009) suggested that an endogenous negative regulatory role for the PIK3R-FGFR3 interaction on the Ras/ERK/MAPK pathway may exist in response to FGFR3 activity. </p><p>Using mouse embryonic fibroblasts, Park et al. (2010) showed that, in addition to regulating PI3K function, p85-alpha and p85-beta regulated the function of Xbp1s (XBP1; 194355), a transcription factor that orchestrates the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress. Both p85-alpha and p85-beta bound Xbp1s and increased its nuclear translocation, and it appeared that the p110 PI3K catalytic subunit and Xbp1s competed for binding of these regulatory subunits. p85-alpha and p85-beta formed an inactive dimer that was disrupted by insulin in a time-dependent manner, which promoted their association with Xbp1s. Refeeding of wildtype mice after fasting induced ER stress that was quickly resolved, as measured by Xbp1s levels. In contrast, obese and insulin-resistant ob/ob (LEP; 164160) mice could not resolve the ER stress induced during refeeding, and nuclear translocation of Xbp1s was absent in ob/ob mice. Overexpression of p85-alpha or p85-beta in livers of ob/ob mice increased glucose tolerance and reduced blood glucose concentrations. </p><p>Independently, Winnay et al. (2010) found that p85-alpha interacted with Xbp1 in an ER stress-dependent manner in mice and that this interaction was essential in the ER stress response. Cells deficient in p85-alpha or mouse livers with selective inactivation of p85-alpha showed reduced ER stress-dependent accumulation of nuclear Xbp1s and attenuated induction of UPR target genes. </p><p>Using yeast 2-hybrid analysis, pull-down assays, and immunofluorescence analysis, Chiu et al. (2014) found that human BRD7 (618489) interacted with p85-alpha and induced its nuclear translocation. Formation of the BRD7-p85-alpha complex depended on a p85-binding domain in the highly conserved C terminus of BRD7, whereas the nuclear localization of the BRD7-p85-alpha complex depended on the nuclear localization signal of BRD7. The BRD7-p85-alpha complex associated with chromatin. The BRD7-binding region of p85-alpha was the same region used for interaction with p110. Consequently, BRD7 competed with p110 for binding and interacted with free p85-alpha, but not with p85/p110 complexes, and BRD7 did not translocate p110 into the nucleus with BRD7. BRD7 removed p85-alpha from the cytosol to prevent formation of the p85/p110 complex, thereby destabilizing p110 proteins and reducing PI3K signaling. Knockdown of BRD7 increased p110 protein levels, decreased the fraction of p85-alpha in nucleus, and enhanced PI3K signaling. </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>Biochemical Features</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>Crystal Structure</em></strong></p><p>
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Miled et al. (2007) used crystallographic and biochemical approaches to gain insight into activating mutations in 2 noncatalytic p100-alpha domains--the adaptor-binding and the helical domains. A structure of the adaptor-binding domain of p110-alpha (171834) in a complex with the p85-alpha inter-Src homology 2 (inter-SH2) domains shows that the oncogenic mutations in the adaptor-binding domain are not at the inter-SH2 interface but in a polar surface patch that is a plausible docking site for other domains in the holo p110/p85 complex. The authors also examined helical domain mutations and found that the glu545-to-lys (E545K) oncogenic mutant disrupts an inhibitory charge-charge interaction with the p85 N-terminal SH2 domain. Miled et al. (2007) concluded that their studies extended understanding of the architecture of the phosphatidylinositol 3-kinases and provided insight into how 2 classes of mutations that cause a gain of function can lead to cancer. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Cannizzaro et al. (1991) demonstrated that the GRB1 gene is located at 5q13 by analysis of its segregation in rodent-human hybrids and by chromosome in situ hybridization. Cannizzaro et al. (1991) observed that the RASA gene (139150), encoding another receptor-associated signal transducing protein, is also located in 5q13. Volinia et al. (1992) confirmed the mapping of PIK3R1 to chromosome 5q12-q13. Hoyle et al. (1994) demonstrated that the homologous gene in the mouse, Pik3r1, maps to chromosome 13. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Agammaglobulinemia 7, Autosomal Recessive</em></strong></p><p>
|
|
In a patient with autosomal recessive agammaglobulinemia-7 (AGM7; 615214), Conley et al. (2012) identified a homozygous truncating variant in the PIK3R1 gene (W298X; 171833.0001). The mutation, which was identified by exome sequencing, segregated with the disorder and was not found in 1,000 in-house control alleles. Screening of the PIK3R1 gene in 55 additional patients with defects in B-cell development did not identify any other mutations. </p><p><strong><em>SHORT Syndrome, Autosomal Dominant</em></strong></p><p>
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By whole-exome sequencing in 2 unrelated patients with SHORT syndrome (269880), Thauvin-Robinet et al. (2013) identified de novo mutations in the PIK3R1 gene (171833.0002 and 171833.0003). Screening PIK3R1 for mutations in 4 more affected individuals from 3 families revealed a recurrent substitution (R649W; 171833.0004) in all 4 patients. Sequencing PIK3R1 in a heterogeneous clinical group of 14 additional unrelated individuals with severe insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation, who had not previously been diagnosed with SHORT syndrome and who were negative for mutation in known lipodystrophy-associated genes, identified 3 with mutations in PIK3R1, including 1 with the recurrent R649W substitution and another with a 1-bp duplication at R649 (171833.0005). Thauvin-Robinet et al. (2013) noted that the c.1945C-T (R649W) mutation occurred within the context of a CpG dinucleotide, which might explain its recurrence. </p><p>In a 3-generation Norwegian family and in a German mother and son with SHORT syndrome, Chudasama et al. (2013) identified heterozygosity for the R649W missense mutation in the PIK3R1 gene. Haplotype analysis showed that the mutations resided on different backgrounds in the 2 families, indicating that they stemmed from 2 independent mutational events. </p><p>Dyment et al. (2013) performed whole-exome sequencing in a girl with SHORT syndrome and her unaffected parents and identified a frameshift mutation in the PIK3R1 gene (171833.0006) that segregated with disease. Analysis of PIK3R1 in 3 more SHORT probands revealed the presence of the R649W mutation in an affected mother and 2 sons from an English family and in another patient. A PIK3R1 nonsense mutation was identified in the third patient. </p><p><strong><em>Immunodeficiency 36 With Lymphoproliferation, Autosomal Dominant</em></strong></p><p>
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In 4 patients from 3 unrelated families with autosomal dominant immunodeficiency-36 with lymphoproliferation (IMD36; 616005), Deau et al. (2014) identified heterozygous mutations in the PIK3R1 gene (171833.0007 and 171833.0008). The mutations, which were found by whole-exome sequencing, affected the same nucleotide and resulted in the same splicing defect. The mutations were predicted to cause a loss of p85-mediated inhibition of p110 activity, and patient lymphocytes showed increased PI3K activity and enhanced phosphorylation of AKT, consistent with a gain of function. The phenotype was similar to that of patients with IMD14 (615513) carrying gain-of-function mutations in the PIK3CD gene (602839). Patients had decreased amounts of naive T cells and memory B cells, as well as hypogammaglobulinemia. The findings suggested that PI3K activity is tightly regulated in T and B lymphocytes and that various defects in the PI3K-triggered pathway can cause primary immunodeficiencies. </p><p>In 4 patients from 3 unrelated families with immunodeficiency, Lucas et al. (2014) identified heterozygosity for point mutations in the PIK3R1 gene at the same splice donor site that was previously reported in immunodeficient patients by Deau et al. (2014): c.1425+1G-C (171833.0008) in 3 patients from 2 families, and c.1425+1G-A (171833.0009) in the remaining proband. </p><p>In 4 unrelated children with immunodeficiency and a hyper-IGM (see 308230)-like phenotype, who also exhibited poor growth and lymphoproliferation, Lougaris et al. (2015) identified heterozygosity for de novo mutations in the PIK3R1 gene at the same previously reported splice site, c.1425+1G (see 171833.0007 and 171833.0009). </p><p>Petrovski et al. (2016) reported 4 unrelated children with immunodeficiency and elevated IgM levels, lymphadenopathy, and short stature, who all carried the c.1425+1G-A mutation in the PIK3R1 gene (171833.0009). One of the patients exhibited features of SHORT syndrome; the authors noted that no results of immune studies had been reported for SHORT syndrome patients. Functional analysis showed that the splice site mutation results in deletion of exon 11 and constitutive activation of PI3K signaling. The authors noted that despite the limited allelic heterogeneity, there was considerable phenotypic heterogeneity in clinical and immunologic abnormalities in patients with PIK3R1-associated immunodeficiency. </p><p>Elkaim et al. (2016) studied 36 patients with PIK3R1-associated immunodeficiency, including 8 previously reported patients (Deau et al., 2014; Lucas et al., 2014), and noted that the previously described substitutions at c.1425+1 were detected in 84% of patients, with G-A identified in 42%, G-C in 29%, and G-T in 13%. Four additional patients had mutations involving c.1425+2, including 2 with a T-A substitution (171833.0010), 1 with a T-G substitution (171833.0011), and 1 with a TG deletion (171833.0012). Another patient had a G-C substitution at the -1 position of the splice acceptor site of exon 11 (171833.0013). Analysis of patient mRNA demonstrated that all of the mutations cause skipping of exon 11 (coding exon 10). </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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Phosphatidylinositol 3-kinase is a key step in the metabolic actions of insulin. Two amino acid polymorphisms have been identified in the regulatory subunit of p85-alpha, met326 to ile and asn330 to asp. The former is associated with alterations in glucose/insulin homeostasis. Almind et al. (2002) presented observations indicating that the met326-to-ile variant of p85-alpha is functional for intracellular signaling and adipocyte differentiation but has small alterations in protein expression and activity that could play a role in modifying insulin action. These conclusions were based on studies where the 4 human p85-alpha proteins encoded by these 4 alleles were expressed in yeast. </p><p><strong><em>Somatic Mutations</em></strong></p><p>
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The Cancer Genome Atlas Research Network (2008) reported the interim integrative analysis of DNA copy number, gene expression, and DNA methylation aberrations in 206 glioblastomas and nucleotide sequence alterations in 91 of the 206 glioblastomas. The authors observed that the RTK/RAS/PI3K signaling pathway was altered in 88% of glioblastomas. Somatic mutation in the PI3K complex was frequently identified. In particular, novel somatic mutations were identified in the PIK3R1 gene that resulted in disruption of the important C2-iSH2 interaction between PIK3R1 and PIK3CA (171834). </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>Phosphoinositide 3-kinase (PI3K) activation is implicated in many responses, including fibroblast growth, transformation, survival, and chemotaxis. Although PI3K is activated by several agents that stimulate T and B cells, the role of PI3K in lymphocyte function remained to be clarified. Fruman et al. (1999) disrupted the mouse gene encoding the PI3K adaptor subunit p85-alpha and its splice variants p55-alpha and p50-alpha. Most mice homozygous for disruption for all 3 variants died within days after birth. Lymphocyte development and function were studied with the use of the RAG2-deficient blastocyst complementation system. Chimeric mice had reduced numbers of peripheral mature B cells and decreased serum immunoglobulin. The B cells that developed had diminished proliferative responses to antibody to immunoglobulin M, antibody to CD40, and lipopolysaccharide stimulation, as well as decreased survival after incubation with interleukin-4. In contrast, T-cell development and proliferation were normal. This phenotype was similar to defects observed in mice lacking the tyrosine kinase Btk and in patients with Bruton X-linked agammaglobulinemia (300300). </p><p>Suzuki et al. (1999) found that mice with a targeted gene disruption of p85-alpha had impaired B-cell development at the pro-B cell stage, reduced numbers of mature B cells and peritoneal CD5+ Ly-1 B cells, reduced B-cell proliferative responses, and no T cell-independent antibody production. These phenotypes were nearly identical to those of the mutant X-linked immunodeficiency (xid) mouse and of mice in whom the Btk gene has been disrupted. These results provided evidence that p85-alpha is functionally linked to the Btk pathway in antigen receptor-mediated signal transduction and is pivotal in B-cell development and functions. </p><p>Terauchi et al. (1999) reported that Pik3r1 -/- mice show increased insulin sensitivity and hypoglycemia due to increased glucose transport in skeletal muscle and adipocytes. Insulin-stimulated PI3K activity associated with insulin receptor substrates was mediated by full-length p85-alpha in wildtype mice, but by the p50-alpha alternative splicing isoform of the same gene in Pik3r1 -/- mice. This isoform switch was associated with an increase in insulin-induced generation of phosphatidylinositol(3,4,5)triphosphate in Pik3r1 -/- adipocytes and facilitation of Glut4 (138190) translocation from the low density microsome fraction to the plasma membrane. This mechanism seemed to be responsible for the phenotype of the homozygous deficient mice, namely increased glucose transport and hypoglycemia. This work provided the first direct evidence that PI3K and its regulatory subunits have a role in glucose homeostasis in vivo. </p><p>Taniguchi et al. (2006) found that mice with a liver-specific deletion of Pik3r1 showed increased hepatic and peripheral insulin sensitivity. Pik3r1 ablation resulted in improved Akt activation, in part, because of decreased activity of the (3,4,5)-trisphosphate phosphatase Pten (601728). The authors concluded that Pik3r1 is a critical modulator of insulin sensitivity not only because of its effect on PI3K activation, but also as a regulator of PTEN activity. </p><p>Fukao et al. (2002) found that mice lacking p85-alpha were severely deficient in gastrointestinal and peritoneal mast cells, whereas dermal mast cells were present in the skin. The p85-alpha -/- mice were susceptible to acute septic peritonitis. However, they were also susceptible to systemic anaphylaxis, reflecting the absence of peritoneal mast cells but the presence of mast cells at other anatomic sites. Reconstitution of the mutant mice with bone marrow-derived mast cells (BMMCs) restored antibacterial immunity but not immunity to an intestinal nematode. Treatment of the BMMCs with Th2 lymphocyte-derived cytokines, i.e. IL4 (147780) and IL10 (124092), induced immunity to the parasitic worm, probably because mesenteric lymph node cells from the p85-alpha -/- mice produced reduced amounts of these cytokines. Fukao et al. (2002) concluded that PI3K plays an essential role in the development and induction of mast cells in normal and pathogenic immune responses. </p><p>Fukao et al. (2002) found that Pik3r1-deficient mice showed enhanced Th1-type responses after Leishmania major infection. Normal splenic dendritic cells (DCs) responded to IL12 (see 161561) production-inducing stimuli with concomitant Pi3k activation. Splenic DCs from mutant mice or normal DCs treated with a Pi3k inhibitor showed increased IL12 production and reduced Th2 cytokine production. Because Pi3k inhibition and Pik3r1 deficiency resulted in enhanced IL12 production, Fukao et al. (2002) proposed that Pi3k is a negative regulator of IL12 production and that Pi3k inhibition may prevent potential immunopathologic effects of strong Th1 responses resulting from excessive IL12 production. </p><p>Oak et al. (2006) crossed mice with a floxed Pik3r1 allele and a null Pik3r2 allele with Lck (153390)-Cre transgenic mice to generate a strain in which class IA Pi3k expression and function were essentially abrogated in T cells beginning at the double-negative stage. Histopathologic analysis of these mice showed development of organ-specific autoimmunity resembling Sjogren syndrome (SS; 270150). By 3 to 8 months of age, mutant mice developed corneal opacity and eye lesions due to irritation and constant scratching. Mutant mice showed marked lymphocytic infiltration of lacrimal glands and serum antinuclear and anti-Ssa (SSA1; 109092) antibodies, but no kidney pathology. Cd4-positive T cells, which were the predominant infiltrating cells in lacrimal glands of mutant mice, exhibited aberrant differentiation in vitro. Oak et al. (2006) concluded that impaired class IA PI3K signaling in T cells can lead to organ-specific autoimmunity, and they proposed that class IA Pi3k-deficient mice manifest the cardinal features of human primary SS. </p>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>13 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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<h4>
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<span class="mim-font">
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<strong>.0001 AGAMMAGLOBULINEMIA 7, AUTOSOMAL RECESSIVE (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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PIK3R1, TRP298TER
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<br />
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SNP: rs397509384,
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ClinVar: RCV000041966, RCV001388977
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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 19-year-old girl with agammaglobulinemia-7 (AGM7; 615214) and a severe defect in early B-cell development, Conley et al. (2012) identified a homozygous G-to-A transition in exon 6 of the PIK3R1 gene, resulting in a trp298-to-ter (W298X) substitution in the Rac binding domain. The patient was from a consanguineous family of Chinese/Peruvian descent and had previously been reported by de la Morena et al. (1995) as having an autosomal recessive immunodeficiency reminiscent of Bruton agammaglobulinemia (300755). Each unaffected parent was heterozygous for the mutation, which was found by whole-exome sequencing and was not present in 1,000 in-house control alleles. The mutation resulted in absence of p85 expression, but normal p55 and p50 expression. The patient presented at 3.5 months of age with pneumonia and gastroenteritis. Laboratory studies showed panhypogammaglobulinemia, neutropenia, and decreased NK cells. T cells were essentially normal. As a teenager, she developed erythema nodosum, juvenile idiopathic arthritis, recurrent Campylobacter bacteremia, and inflammatory bowel disease, suggesting disordered cytokine production. The family history was positive for 2 older brothers and 2 maternal uncles who died of acute infections between 9 and 18 months of age. Flow cytometric analysis showed that the patient had near absence of B cells in peripheral blood, and bone marrow aspiration showed normal cellularity with almost complete absence of B lineage cells. However, there were normal percentages of very early CD34+,CD19- B-cell precursors. The patient had no p85 in T cells, neutrophils, or dendritic cells. There was decreased expression of p110 in patient immune cells, indicating that the N-terminal end of p85 contributes to binding and stabilization of p110. Overall, the findings suggested that mutations in the N-terminal region of p85 can result in failure of B-cell development at a very early stage, even earlier than in mouse models. Screening of the PIK3R1 gene in 55 additional patients with defects in B-cell development did not identify any other mutations. </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 SHORT SYNDROME</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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PIK3R1, ILE539DEL
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<br />
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SNP: rs397514046,
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ClinVar: RCV000054532, RCV000623355
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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 7-year-old boy with SHORT syndrome (269880), Thauvin-Robinet et al. (2013) identified heterozygosity for a de novo 3-bp deletion (c.1615_1617delATT) at chr5:67,591,018 (GRCh37) in the PIK3R1 gene, resulting in deletion of ile539 in the inter-Src homology 2 (iSH2) domain. The mutation was not present in his unaffected parents and was not found in the NHLBI Exome Variant Server, dbSNP (build 137), or 1000 Genomes Project databases. Functional studies on patient fibroblasts revealed a 70 to 90% reduction in the effect of insulin on AKT (see 164730) activation, glycogen synthesis, and glucose uptake, indicating severe insulin resistance for both proximal and distal PI3K-dependent signaling. </p>
|
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</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0003 SHORT SYNDROME</strong>
|
|
</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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PIK3R1, GLU489LYS
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<br />
|
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SNP: rs397514047,
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|
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ClinVar: RCV000054533
|
|
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</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a 7-year-old boy with SHORT syndrome (269880), Thauvin-Robinet et al. (2013) identified heterozygosity for a de novo c.1465G-A transition at chr5:67,590,403 (GRCh37) in the PIK3R1 gene, resulting in a glu489-to-lys (E489K) substitution at a highly conserved residue in the inter-Src homology 2 (iSH2) domain. The mutation was not present in his unaffected parents and was not found in the NHLBI Exome Variant Server, dbSNP (build 137), or 1000 Genomes Project databases. Functional studies on patient fibroblasts revealed a 70 to 90% reduction in the effect of insulin on AKT (see 164730) activation, glycogen synthesis, and glucose uptake, indicating severe insulin resistance for both proximal and distal PI3K-dependent signaling. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0004 SHORT SYNDROME</strong>
|
|
</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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PIK3R1, ARG649TRP
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|
<br />
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|
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SNP: rs397515453,
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ClinVar: RCV000054534, RCV000414540, RCV000515192, RCV001197921, RCV001265992
|
|
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|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 patients from 4 families with SHORT syndrome (269880), including a patient previously reported by Bonnel et al. (2000), Thauvin-Robinet et al. (2013) identified heterozygosity for a c.1945C-T transition at chr5:67,592,129 (GRCh37) in the PIK3R1 gene, resulting in an arg649-to-trp (R649W) substitution at a highly conserved residue in the cSH2 domain. In the 1 family for which parental DNA was available, the mutation was shown to be de novo. Thauvin-Robinet et al. (2013) noted that the c.1945C-T mutation occurred within the context of a CpG dinucleotide, which might explain its recurrence. </p><p>In affected members of a 3-generation Norwegian family with SHORT syndrome, originally described by Aarskog et al. (1983), and a German mother and son with SHORT syndrome, originally reported by Koenig et al. (2003), Chudasama et al. (2013) identified heterozygosity for the R649W missense mutation in the PIK3R1 gene. The mutation was not found in 340 Norwegian controls. Haplotype analysis showed that the mutations resided on different backgrounds in the 2 families, indicating that they stemmed from 2 independent mutational events. Analysis of patient fibroblasts and reconstituted Pik3r1-knockout preadipocytes demonstrated impaired interaction between p85-alpha and IRS1 (147545) and reduced AKT (see 164730)-mediated insulin signaling. </p><p>In a mother and 2 sons from an English family with SHORT syndrome, originally reported by Bankier et al. (1995) and restudied by Reardon and Temple (2008), and in an unrelated male patient, Dyment et al. (2013) identified heterozygosity for the R649W mutation in the PIK3R1 gene. </p>
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>.0005 SHORT SYNDROME</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
PIK3R1, 1-BP DUP, 1943T
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<br />
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SNP: rs398122384,
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|
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ClinVar: RCV000054535
|
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 60-year-old woman with severe insulin resistance, generalized lipoatrophy, and facial dysmorphism consistent with SHORT syndrome (269880), Thauvin-Robinet et al. (2013) identified heterozygosity for a 1-bp duplication (c.1943dupT) in the PIK3R1 gene, causing a frameshift predicted to result in a premature termination codon (Arg649ProfsTer5). </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 SHORT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
PIK3R1, 1-BP INS, 1906C
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|
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|
|
|
<br />
|
|
|
|
SNP: rs398122385,
|
|
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|
|
|
|
|
ClinVar: RCV000054536
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 2-year-old girl with SHORT syndrome (269880), Dyment et al. (2013) identified heterozygosity for a de novo 1-bp insertion (c.1906_1907insC) in exon 14 of the PIK3R1 gene, causing a frameshift predicted to generate a premature termination codon (Asn636ThrfsTer18). The mutation was not found in her unaffected parents. Functional analysis of patient lymphoblastoid cells showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT (see 164730)-mTOR (601231) pathway. </p>
|
|
</span>
|
|
</div>
|
|
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|
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|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
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<div>
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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 IMMUNODEFICIENCY 36 WITH LYMPHOPROLIFERATION</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
PIK3R1, IVS11DS, G-T, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777709,
|
|
|
|
|
|
|
|
ClinVar: RCV000144065, RCV000349198, RCV001218386
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with immunodeficiency-36 with lymphoproliferation (IMD36; 616005), Deau et al. (2014) identified a de novo heterozygous G-to-T transversion in intron 10 of the PIK3R1 gene, resulting in an in-frame deletion of exon 10 and removal of a peptide sequence (amino acid residues 434-475) that is part of an alpha-helix involved in p110 binding. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database or in an in-house control database. The same splice site mutation, resulting from a different nucleotide change (171833.0008), was found in 3 additional patients with a similar disorder. Both mutations resulted in a loss of p85-mediated inhibition and caused increased phosphorylation of downstream signaling pathways, consistent with a gain of function. Immunologic studies showed a defect in both B- and T-cell differentiation. </p><p>Lucas et al. (2014) designated the c.1425+1 splice site as occurring in intron 11 of the PIK3R1 gene (c.1425+1G-T, NM_181523.2). </p><p>In a 19-month-old Italian girl with recurrent respiratory infections and poor growth, who had hypogammaglobulinemia with elevated serum IgM levels and lymphoproliferation, Lougaris et al. (2015) identified heterozygosity for the c.1425+1G-T splice site mutation in the PIK3R1 gene. The mutation occurred de novo. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 IMMUNODEFICIENCY 36 WITH LYMPHOPROLIFERATION</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PIK3R1, IVS11DS, G-C, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777709,
|
|
|
|
|
|
|
|
ClinVar: RCV000144066, RCV000508456, RCV000623166, RCV000800719, RCV003156075
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 patients from 2 unrelated families with immunodeficiency-36 with lymphoproliferation (IMD36; 616005), Deau et al. (2014) identified a heterozygous G-to-C transversion in intron 10 of the PIK3R1 gene, resulting in an in-frame deletion of exon 10 and removal of a peptide sequence (amino acids 434-475) that is part of an alpha-helix involved in p110 binding. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database or in an in-house control database. In 1 family, a mother and child were affected. The same splice site mutation, resulting from a different nucleotide change (171833.0007), was found in another patient with a similar disorder. Both mutations resulted in a loss of p85-mediated inhibition and caused increased phosphorylation of downstream signaling pathways, consistent with a gain of function. Immunologic studies showed a defect in both B- and T-cell differentiation. </p><p>In a 32-year-old Turkish woman and a Caucasian American mother and son with immunodeficiency, Lucas et al. (2014) identified heterozygosity for the c.1425+1G-C mutation, which they designated as occurring in intron 11 of the PIK3R1 gene (c.1425+1G-C, NM_181523.2). Sequencing of patient cDNA demonstrated that the mutation causes skipping of exon 11, resulting in an in-frame deletion of residues 434 to 475 of the p85-alpha regulatory subunit. Analysis of PI3K signaling in patient T-cell blasts showed increased phosphorylation of AKT (164730) and downstream targets compared to controls, indicating constitutive hyperactivation of PI3K and AKT. The mutant p85-alpha protein was detected at low levels in patient cells, and overexpression of the mutant in control T cells demonstrated a dominant gain-of-function effect on PI3K signaling. In addition, the authors showed that this hyperactivation is due to qualitatively and quantitatively different binding to, and impaired inhibition of, the p110-delta catalytic subunit (PIK3CD; 602839). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 IMMUNODEFICIENCY 36 WITH LYMPHOPROLIFERATION</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PIK3R1, IVS11DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777709,
|
|
|
|
|
|
|
|
ClinVar: RCV000413301, RCV000515768, RCV000705809, RCV000987525, RCV001027613, RCV001266930, RCV003156092, RCV003922673
|
|
|
|
|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 5-year-old Chinese boy with immunodeficiency-36 with lymphoproliferation (IMD36; 616005), who also exhibited lymphadenopathy, hepatomegaly, and severe juvenile rheumatoid arthritis, Lucas et al. (2014) identified heterozygosity for a c.1425+1G-A mutation (c.1425+1G-A, NM_181523.2) in intron 11 of the PIK3R1 gene. </p><p>In a 9-month-old Albanian girl, a 3-year-old Italian boy, and a 3.5-year-old Swedish girl with recurrent respiratory infections and poor growth, who had hypogammaglobulinemia with elevated serum IgM levels and lymphoproliferation, Lougaris et al. (2015) identified heterozygosity for the c.1425+1G-A mutation in the PIK3R1 gene. The mutation was shown to have occurred de novo in 2 of the patients; the genotype of the Swedish parents was unknown. </p><p>In 4 unrelated children (patients 1-4) with immunodeficiency and elevated IgM levels, lymphadenopathy, and short stature, Petrovski et al. (2016) identified heterozygosity for the c.1425+1G-A mutation in PIK3R1. The mutation was confirmed to have arisen de novo in 3 of the patients; it was not found in the fourth child's unaffected mother, but DNA was unavailable from the father. Analysis of PCR products from patient 1 and his parents demonstrated that the mutation causes skipping of exon 11, with direct exon 10 to exon 12 splicing. Results of functional analysis using patient cells were consistent with constitutive activation of the PI3K-mTOR (601231) signaling. Patient 4, a 5-year-old Caucasian girl, also exhibited features of SHORT syndrome (269880); the authors noted that no results of immune studies had been reported for SHORT syndrome patients. </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>
|
|
<span class="mim-font">
|
|
<strong>.0010 IMMUNODEFICIENCY 36 WITH LYMPHOPROLIFERATION</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
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|
PIK3R1, IVS11DS, T-A, +2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1554051075,
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|
|
|
|
ClinVar: RCV000515774, RCV002527446
|
|
|
|
|
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</span>
|
|
</div>
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 patients with immunodeficiency-36 with lymphoproliferation (IMD36; 616005), Elkaim et al. (2016) identified heterozygosity for a c.1425+2T-A transversion (c.1425+2T-A, NM_181523.2) in intron 11 of the PIK3R1 gene. Analysis of patient mRNA demonstrated skipping of exon 11 (coding exon 10), encoding amino acids 434 to 475 of p85-alpha. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 IMMUNODEFICIENCY 36 WITH LYMPHOPROLIFERATION</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
PIK3R1, IVS11DS, T-G, +2
|
|
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|
|
<br />
|
|
|
|
SNP: rs1554051075,
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|
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|
|
ClinVar: RCV000515763, RCV001815343
|
|
|
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|
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</span>
|
|
</div>
|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient (P8) with immunodeficiency-36 with lymphoproliferation (IMD36; 616005), Elkaim et al. (2016) identified heterozygosity for a c.1425+2T-G transversion (c.1425+2T-G, NM_181523.2) in intron 11 of the PIK3R1 gene. Analysis of patient mRNA demonstrated skipping of exon 11 (coding exon 10), encoding amino acids 434 to 475 of p85-alpha. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0012 IMMUNODEFICIENCY 36 WITH LYMPHOPROLIFERATION</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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PIK3R1, IVS11, 2-BP DEL, +2TG
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<br />
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SNP: rs1554051067,
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ClinVar: RCV000515770
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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 patient (P10) with immunodeficiency-36 with lymphoproliferation (IMD36; 616005), Elkaim et al. (2016) identified heterozygosity for a 2-bp deletion (c.1425+2delTG, NM_181523.2) in intron 11 of the PIK3R1 gene. Analysis of patient mRNA demonstrated skipping of exon 11 (coding exon 10), encoding amino acids 434 to 475 of p85-alpha. </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>.0013 IMMUNODEFICIENCY 36 WITH LYMPHOPROLIFERATION</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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PIK3R1, IVS10AS, G-C, -1
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<br />
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SNP: rs1554051033,
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ClinVar: RCV000515775
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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 patient (P19) with immunodeficiency-36 with lymphoproliferation (IMD36; 616005), Elkaim et al. (2016) identified heterozygosity for a c.1300-1G-C transversion (c.1300-1G-C, NM_181523.2) in intron 10 of the PIK3R1 gene. Analysis of patient mRNA demonstrated skipping of exon 11 (coding exon 10), encoding amino acids 434 to 475 of p85-alpha. </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>REFERENCES</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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<strong>The regulatory subunits of PI3K, p85-alpha and p85-beta, interact with XBP-1 and increase its nuclear translocation.</strong>
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