4331 lines
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Entry
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- *300079 - INHIBITOR OF APOPTOSIS, X-LINKED; XIAP
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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">*300079</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<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/300079">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div 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=ENSG00000101966;t=ENST00000371199" 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=331" 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=300079" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<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=ENSG00000101966;t=ENST00000371199" 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_001167,NM_001204401,NM_001378590,NM_001378591,NM_001378592,NR_037916,NR_165803" 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_001167" 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=300079" 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 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=02094&isoform_id=02094_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/XIAP" 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/1016688,12643387,21619764,32528299,58003502,119632263,119632264,119632265,119632266,189067016,219752963,219752981,324711009,1811637074,1811637186,1811637201" 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/P98170" 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=331" 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=ENSG00000101966;t=ENST00000371199" 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=XIAP" 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=XIAP" 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+331" 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/XIAP" 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:331" 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/331" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chrX&hgg_gene=ENST00000371199.8&hgg_start=123859708&hgg_end=123913972&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:592" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/xiap" 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=300079[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=300079[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000101966" 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=XIAP" 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=XIAP" 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=XIAP" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/XIAP" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=XIAP&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/PA25361" 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:592" 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/FBgn0015247.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:107572" 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/XIAP#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:107572" 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/331/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=331" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030825-7" 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:331" 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=XIAP&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1162830004<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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300079
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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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INHIBITOR OF APOPTOSIS, X-LINKED; XIAP
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
BACULOVIRAL IAP REPEAT-CONTAINING PROTEIN 4; BIRC4<br />
|
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APOPTOSIS INHIBITOR 3; API3<br />
|
|
IAP-LIKE PROTEIN; ILP<br />
|
|
MAMMALIAN IAP HOMOLOG A; MIHA
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=XIAP" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">XIAP</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
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<em>
|
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Cytogenetic location: <a href="/geneMap/X/652?start=-3&limit=10&highlight=652">Xq25</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:123859708-123913972&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">X:123,859,708-123,913,972</a> </span>
|
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</em>
|
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
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|
<tr>
|
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<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/652?start=-3&limit=10&highlight=652">
|
|
Xq25
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Lymphoproliferative syndrome, X-linked, 2
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/300635"> 300635 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/300079" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/300079" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
|
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</div>
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<div>
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<p>The XIAP gene belongs to the 'inhibitor of apoptosis protein' (IAP) gene family, which also includes HIAP1 (<a href="/entry/601721">601721</a>), and HIAP2 (<a href="/entry/601712">601712</a>). XIAP has a capacity to block apoptosis by directly inhibiting certain caspases. In addition to its antiapoptotic function, XIAP is involved in a variety of signaling pathways and/or cellular responses through ubiquitylation or as a signal transducer for the Nod-like receptors NOD1 (<a href="/entry/605980">605980</a>) and NOD2 (<a href="/entry/605956">605956</a>), which play a role in innate immunity (review by <a href="#14" class="mim-tip-reference" title="Latour, S., Aguilar, C. <strong>XIAP deficiency syndrome in humans.</strong> Semin. Cell Dev. Biol. 39: 115-123, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25666262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25666262</a>] [<a href="https://doi.org/10.1016/j.semcdb.2015.01.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25666262">Latour and Aguilar, 2015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25666262" 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="Duckett, C. S., Nava, V. E., Gedrich, R. W., Clem, R. J., Van Dongen, J. L., Gilfillan, M. C., Shiels, H., Hardwick, J. M., Thompson, C. B. <strong>A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors.</strong> EMBO J. 15: 2685-2694, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8654366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8654366</a>]" pmid="8654366">Duckett et al. (1996)</a> cloned the XIAP gene, which they referred to as hILP, for 'human IAP-like protein.' They reported that the gene encodes a 497-amino acid polypeptide with a predicted mass of 57 kD. They further noted that the sequence contains BIRs (baculovirus IAP repeats) and RING finger domains. <a href="#6" class="mim-tip-reference" title="Duckett, C. S., Nava, V. E., Gedrich, R. W., Clem, R. J., Van Dongen, J. L., Gilfillan, M. C., Shiels, H., Hardwick, J. M., Thompson, C. B. <strong>A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors.</strong> EMBO J. 15: 2685-2694, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8654366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8654366</a>]" pmid="8654366">Duckett et al. (1996)</a> considered data gleaned from EST database analysis to be evidence that hILP is one of several human genes related to IAP. <a href="#6" class="mim-tip-reference" title="Duckett, C. S., Nava, V. E., Gedrich, R. W., Clem, R. J., Van Dongen, J. L., Gilfillan, M. C., Shiels, H., Hardwick, J. M., Thompson, C. B. <strong>A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors.</strong> EMBO J. 15: 2685-2694, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8654366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8654366</a>]" pmid="8654366">Duckett et al. (1996)</a> expressed hILP in mammalian cell lines and found that it was able to block virally induced apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8654366" 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="#26" class="mim-tip-reference" title="Uren, A. G., Pakusch, M., Hawkins, C. J., Puls, K. L., Vaux, D. L. <strong>Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors.</strong> Proc. Nat. Acad. Sci. 93: 4974-4978, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8643514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8643514</a>] [<a href="https://doi.org/10.1073/pnas.93.10.4974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8643514">Uren et al. (1996)</a> reported that XIAP, which they called MIHA, shares 43% protein sequence identity with HIAP1 and HIAP2. <a href="#26" class="mim-tip-reference" title="Uren, A. G., Pakusch, M., Hawkins, C. J., Puls, K. L., Vaux, D. L. <strong>Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors.</strong> Proc. Nat. Acad. Sci. 93: 4974-4978, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8643514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8643514</a>] [<a href="https://doi.org/10.1073/pnas.93.10.4974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8643514">Uren et al. (1996)</a> determined that expression of XIAP in mammalian cells significantly reduced ICE (<a href="/entry/147678">147678</a>)-mediated apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8643514" 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="Liston, P., Roy, N., Tamai, K., Lefebvre, C., Baird, S., Cherton-Horvat, G., Farahani, R., McLean, M., Ikeda, J.-E., MacKenzie, A., Korneluk, R. G. <strong>Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes.</strong> Nature 379: 349-353, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8552191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8552191</a>] [<a href="https://doi.org/10.1038/379349a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8552191">Liston et al. (1996)</a> found that XIAP inhibited serum deprivation-induced apoptosis and apoptosis triggered by treatment with menadione, a potent inducer of free radicals. Northern blot analysis revealed XIAP expression as a 9-kb mRNA in all fetal and adult tissues tested except peripheral blood leukocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8552191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Farahani, R., Fong, W. G., Korneluk, R. G., MacKenzie, A. E. <strong>Genomic organization and primary characterization of miap-3: the murine homologue of human X-linked IAP.</strong> Genomics 42: 514-518, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9205126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9205126</a>] [<a href="https://doi.org/10.1006/geno.1997.4742" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9205126">Farahani et al. (1997)</a> isolated cDNAs encoding miap3, the mouse XIAP homolog. The predicted 496-amino acid mouse protein is 94% identical to human XIAP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9205126" 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="#4" class="mim-tip-reference" title="Deveraux, Q. L., Takahashi, R., Salvesen, G. S., Reed, J. C. <strong>X-linked IAP is a direct inhibitor of cell-death proteases.</strong> Nature 388: 300-304, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9230442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9230442</a>] [<a href="https://doi.org/10.1038/40901" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9230442">Deveraux et al. (1997)</a> showed that human X-linked IAP directly inhibits at least 2 members of the caspase family of cell-death proteases, caspase-3 (CASP3; <a href="/entry/600636">600636</a>) and caspase-7 (CASP7; <a href="/entry/601761">601761</a>). As the caspases are highly conserved throughout the animal kingdom and are the principal effectors of apoptosis, these findings suggested how IAPs might inhibit cell death, providing evidence for a mechanism of action for these mammalian cell-death suppressors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9230442" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To determine why proteasome inhibitors prevent thymocyte death, <a href="#30" class="mim-tip-reference" title="Yang, Y., Fang, S., Jensen, J. P., Weissman, A. M., Ashwell, J. D. <strong>Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli.</strong> Science 288: 874-877, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10797013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10797013</a>] [<a href="https://doi.org/10.1126/science.288.5467.874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10797013">Yang et al. (2000)</a> examined whether proteasomes degrade antiapoptotic molecules in cells induced to undergo apoptosis. The HIAP2 and XIAP inhibitors of apoptosis were selectively lost in glucocorticoid- or etoposide-treated thymocytes in a proteasome-dependent manner before death. IAPs catalyzed their own ubiquitination in vitro, an activity requiring the RING domain. Overexpressed wildtype HIAP2, but not a RING domain mutant, was spontaneously ubiquitinated and degraded, and stably expressed XIAP lacking the RING domain was relatively resistant to apoptosis-induced degradation and, correspondingly, more effective at preventing apoptosis than wildtype XIAP. <a href="#30" class="mim-tip-reference" title="Yang, Y., Fang, S., Jensen, J. P., Weissman, A. M., Ashwell, J. D. <strong>Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli.</strong> Science 288: 874-877, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10797013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10797013</a>] [<a href="https://doi.org/10.1126/science.288.5467.874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10797013">Yang et al. (2000)</a> concluded that autoubiquitination and degradation of IAPs may be a key event in the apoptotic program. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10797013" 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>XIAP interacts with caspase-9 (CASP9; <a href="/entry/602234">602234</a>) and inhibits its activity, whereas SMAC (<a href="/entry/605219">605219</a>) relieves this inhibition through interaction with XIAP. <a href="#24" class="mim-tip-reference" title="Srinivasula, S. M., Hegde, R., Saleh, A., Datta, P., Shiozaki, E., Chai, J., Lee, R.-A., Robbins, P. D., Fernandes-Alnemri, T., Shi, Y., Alnemri, E. S. <strong>A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis.</strong> Nature 410: 112-116, 2001. Note: Erratum: Nature 411: 1081 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242052</a>] [<a href="https://doi.org/10.1038/35065125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242052">Srinivasula et al. (2001)</a> demonstrated that XIAP associates with the active caspase-9-APAF1 (<a href="/entry/602233">602233</a>) holoenzyme complex through binding to the amino terminus of the linker peptide on the small subunit of caspase-9, which becomes exposed after proteolytic processing of procaspase-9 at asp315. Supporting this observation, point mutations that abrogate the proteolytic processing but not the catalytic activity of caspase-9, or deletion of the linker peptide, prevented caspase-9 association with XIAP and its concomitant inhibition. <a href="#24" class="mim-tip-reference" title="Srinivasula, S. M., Hegde, R., Saleh, A., Datta, P., Shiozaki, E., Chai, J., Lee, R.-A., Robbins, P. D., Fernandes-Alnemri, T., Shi, Y., Alnemri, E. S. <strong>A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis.</strong> Nature 410: 112-116, 2001. Note: Erratum: Nature 411: 1081 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242052</a>] [<a href="https://doi.org/10.1038/35065125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242052">Srinivasula et al. (2001)</a> noted that the N-terminal 4 residues of caspase-9 linker peptide share significant homology with the N-terminal tetrapeptide in mature SMAC and in the Drosophila proteins Hid/Grim/Reaper, defining a conserved class of IAP-binding motifs. Consistent with this finding, binding of the caspase-9 linker peptide and SMAC to the BIR3 domain of XIAP is mutually exclusive, suggesting that SMAC potentiates caspase-9 activity by disrupting the interaction of the linker peptide of caspase-9 with BIR3. <a href="#24" class="mim-tip-reference" title="Srinivasula, S. M., Hegde, R., Saleh, A., Datta, P., Shiozaki, E., Chai, J., Lee, R.-A., Robbins, P. D., Fernandes-Alnemri, T., Shi, Y., Alnemri, E. S. <strong>A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis.</strong> Nature 410: 112-116, 2001. Note: Erratum: Nature 411: 1081 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242052</a>] [<a href="https://doi.org/10.1038/35065125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242052">Srinivasula et al. (2001)</a> concluded that their studies reveal a mechanism in which binding to the BIR3 domain of XIAP by 2 conserved peptides, one from SMAC and the other from caspase-9, has opposing effects on caspase activity and apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242052" 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>IKKB (<a href="/entry/603258">603258</a>) is required for NFKB (see <a href="/entry/164011">164011</a>) activation by TNFA (<a href="/entry/191160">191160</a>), whereas IKKA (<a href="/entry/600664">600664</a>) is dispensable. Using immune complex kinase assays to measure the effect of TNFA on the activities of IKK and JNK (e.g., <a href="/entry/602897">602897</a>) in wildtype or RelA (<a href="/entry/164014">164014</a>)-, IKKA-, or IKKB-deficient mouse embryonic fibroblasts, <a href="#25" class="mim-tip-reference" title="Tang, G., Minemoto, Y., Dibling, B., Purcell, N. H., Li, Z., Karin, M., Lin, A. <strong>Inhibition of JNK activation through NF-kappa-B target genes.</strong> Nature 414: 313-317, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11713531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11713531</a>] [<a href="https://doi.org/10.1038/35104568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11713531">Tang et al. (2001)</a> found that JNK activation is transient in wildtype and Ikka -/- fibroblasts but sustained in RelA -/- and Ikkb -/- cells. In contrast, IKK activation was also transient but robust in Ikka -/- and wildtype fibroblasts but severely impaired in Ikkb -/- cells. Immunoblot analysis showed that Tnfa induced expression of XIAP in wildtype but not RelA -/- cells, indicating that XIAP is targeted by NFKB. Transient expression of XIAP in HeLa cells inhibited JNK activation by TNFA without affecting JNK expression levels. Expression of a dominant-negative JNKK2 (<a href="/entry/603014">603014</a>) mutant (K149M) or a constitutively active JNKK2-JNK1 (<a href="/entry/601158">601158</a>) fusion protein attenuated or enhanced, respectively, JNK activation and, in RelA -/- fibroblasts, cell death. <a href="#25" class="mim-tip-reference" title="Tang, G., Minemoto, Y., Dibling, B., Purcell, N. H., Li, Z., Karin, M., Lin, A. <strong>Inhibition of JNK activation through NF-kappa-B target genes.</strong> Nature 414: 313-317, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11713531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11713531</a>] [<a href="https://doi.org/10.1038/35104568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11713531">Tang et al. (2001)</a> concluded that IKK negatively modulates JNK activity, most likely through the induction of NFKB target genes encoding proteins such as XIAP, which interfere with TNFA-mediated, but not IL1 (<a href="/entry/147760">147760</a>)-mediated, JNK activation and apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11713531" 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="#22" class="mim-tip-reference" title="Sanna, M. G., Correia, J. S., Luo, Y., Chuang, B., Paulson, L. M., Nguyen, B., Deveraux, Q. L., Ulevitch, R. J. <strong>ILPIP, a novel anti-apoptotic protein that enhances XIAP-mediated activation of JNK1 and protection against apoptosis.</strong> J. Biol. Chem. 277: 30454-30462, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12048196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12048196</a>] [<a href="https://doi.org/10.1074/jbc.M203312200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12048196">Sanna et al. (2002)</a> determined that ILPIP (ALS2CR2; <a href="/entry/607333">607333</a>) potentiates the antiapoptotic activity of XIAP by enhancing XIAP-mediated activation of JNK1 and other JNK family members, but not by modulating XIAP-mediated caspase inhibition. They also found that expression of a catalytically inactive TAK1 (MAP3K7; <a href="/entry/602614">602614</a>) mutant blocked the XIAP/ILPIP activation of JNK1. In vivo coprecipitation experiments showed that both ILPIP and XIAP interact with TAK1 and TRAF6 (<a href="/entry/602355">602355</a>). <a href="#22" class="mim-tip-reference" title="Sanna, M. G., Correia, J. S., Luo, Y., Chuang, B., Paulson, L. M., Nguyen, B., Deveraux, Q. L., Ulevitch, R. J. <strong>ILPIP, a novel anti-apoptotic protein that enhances XIAP-mediated activation of JNK1 and protection against apoptosis.</strong> J. Biol. Chem. 277: 30454-30462, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12048196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12048196</a>] [<a href="https://doi.org/10.1074/jbc.M203312200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12048196">Sanna et al. (2002)</a> concluded that XIAP-mediated protection from apoptosis utilizes both a JNK1 activation pathway that involves ILPIP and a caspase inhibition pathway that is independent of ILPIP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12048196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By targeted deletion, <a href="#3" class="mim-tip-reference" title="Cummins, J. M., Kohli, M., Rago, C., Kinzler, K. W., Vogelstein, B., Bunz, F. <strong>X-linked inhibitor of apoptosis protein (XIAP) is a nonredundant modulator of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human cancer cells.</strong> Cancer Res. 64: 3006-3008, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15126334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15126334</a>] [<a href="https://doi.org/10.1158/0008-5472.can-04-0046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15126334">Cummins et al. (2004)</a> disrupted the XIAP gene in human colon cancer cells. Deletion of the XIAP gene did not interfere with basal proliferation, but it enhanced sensitivity to exogenously added TRAIL (TNFSF10; <a href="/entry/603598">603598</a>). TRAIL increased apoptosis in both XIAP knockout cells and wildtype cells, but the increase was markedly greater in knockout cells. The increased apoptosis in knockout cells correlated with higher levels of cleaved CASP3, but not of CASP7 or CASP9, compared with wildtype cells. Over a broad range of TRAIL doses, XIAP knockout cells exhibited reduced clonogenic survival and proliferation. <a href="#3" class="mim-tip-reference" title="Cummins, J. M., Kohli, M., Rago, C., Kinzler, K. W., Vogelstein, B., Bunz, F. <strong>X-linked inhibitor of apoptosis protein (XIAP) is a nonredundant modulator of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human cancer cells.</strong> Cancer Res. 64: 3006-3008, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15126334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15126334</a>] [<a href="https://doi.org/10.1158/0008-5472.can-04-0046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15126334">Cummins et al. (2004)</a> concluded that XIAP is a nonredundant modulator of TRAIL-mediated apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15126334" 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="Mufti, A. R., Burstein, E., Csomos, R. A., Graf, P. C. F., Wilkinson, J. C., Dick, R. D., Challa, M., Son, J.-K., Bratton, S. B., Su, G. L., Brewer, G. J., Jakob, U., Duckett, C. S. <strong>XIAP is a copper binding protein deregulated in Wilson's disease and other copper toxicosis disorders.</strong> Molec. Cell 21: 775-785, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16543147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16543147</a>] [<a href="https://doi.org/10.1016/j.molcel.2006.01.033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16543147">Mufti et al. (2006)</a> stated that XIAP interacts with and regulates the levels of COMMD1 (<a href="/entry/607238">607238</a>), a protein associated with a form of copper toxicosis in Bedlington terriers. They found that Xiap levels were greatly reduced by intracellular copper accumulation in affected Bedlington terriers, in other dogs with copper toxicosis disorders, in patients with Wilson disease (<a href="/entry/277900">277900</a>), and in human embryonic kidney (HEK293) cells cultured under high copper conditions. Elevated copper levels in HEK293 cells caused a profound, reversible conformational change in endogenous XIAP due to direct binding of copper to XIAP, which accelerated its degradation and significantly decreased its ability to inhibit CASP3, resulting in a lower apoptotic threshold that sensitized the cells to apoptosis. <a href="#17" class="mim-tip-reference" title="Mufti, A. R., Burstein, E., Csomos, R. A., Graf, P. C. F., Wilkinson, J. C., Dick, R. D., Challa, M., Son, J.-K., Bratton, S. B., Su, G. L., Brewer, G. J., Jakob, U., Duckett, C. S. <strong>XIAP is a copper binding protein deregulated in Wilson's disease and other copper toxicosis disorders.</strong> Molec. Cell 21: 775-785, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16543147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16543147</a>] [<a href="https://doi.org/10.1016/j.molcel.2006.01.033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16543147">Mufti et al. (2006)</a> hypothesized that regulation of cell death through XIAP may contribute to the pathophysiology of copper toxicosis disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16543147" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Dohi, T., Xia, F., Altieri, D. C. <strong>Compartmentalized phosphorylation of IAP by protein kinase A regulates cytoprotection.</strong> Molec. Cell 27: 17-28, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17612487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17612487</a>] [<a href="https://doi.org/10.1016/j.molcel.2007.06.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17612487">Dohi et al. (2007)</a> stated that the antiapoptotic function of survivin (BIRC5; <a href="/entry/603352">603352</a>) appears to rely on interactions with other molecules, including XIAP, and that mitochondrial and cytosolic survivin differ with respect to cell death inhibition. Using rat and human cells, <a href="#5" class="mim-tip-reference" title="Dohi, T., Xia, F., Altieri, D. C. <strong>Compartmentalized phosphorylation of IAP by protein kinase A regulates cytoprotection.</strong> Molec. Cell 27: 17-28, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17612487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17612487</a>] [<a href="https://doi.org/10.1016/j.molcel.2007.06.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17612487">Dohi et al. (2007)</a> showed that protein kinase A (see <a href="/entry/176911">176911</a>) phosphorylated survivin in the cytosol, but not in mitochondria. This phosphorylation event disrupted the binding interface between survivin and XIAP. Conversely, mitochondrial survivin or a nonphosphorylatable survivin mutant bound XIAP avidly, enhanced XIAP stability, synergistically inhibited apoptosis, and accelerated tumor growth in immunocompromised mice. <a href="#5" class="mim-tip-reference" title="Dohi, T., Xia, F., Altieri, D. C. <strong>Compartmentalized phosphorylation of IAP by protein kinase A regulates cytoprotection.</strong> Molec. Cell 27: 17-28, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17612487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17612487</a>] [<a href="https://doi.org/10.1016/j.molcel.2007.06.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17612487">Dohi et al. (2007)</a> concluded that differential phosphorylation of survivin by PKA in subcellular microdomains regulates tumor cell apoptosis via its interaction with XIAP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17612487" 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="Kim, J., Park, J., Choi, S., Chi, S.-G., Mowbray, A. L., Jo, H., Park, H. <strong>X-linked inhibitor of apoptosis protein is an important regulator of vascular endothelial growth factor-dependent bovine aortic endothelial cell survival.</strong> Circ. Res. 102: 896-904, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18309102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18309102</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18309102[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/10.1161/CIRCRESAHA.107.163667" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18309102">Kim et al. (2008)</a> showed that ectopic expression of Xiap in bovine aortic endothelial cells blocked Tnf-induced apoptosis by a caspase-independent mechanism. Xiap-associated cell survival was the result of enhanced nitric oxide (NO) production. Xiap partially localized in caveolae, where it interacted via a motif within its BIR3 domain with caveolin-1 (CAV1; <a href="/entry/601047">601047</a>), a regulator of NO production. Endothelial NO synthase (NOS3; <a href="/entry/163729">163729</a>) binding to caveolin-1 was competitively inhibited by Xiap, suggesting that Xiap modulates NO production by releasing endothelial NO synthase from caveolin-1. In addition, Xiap-dependent NO controlled endothelial cell migration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18309102" 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>As summarized by <a href="#12" class="mim-tip-reference" title="Jost, P. J., Grabow, S., Gray, D., McKenzie, M. D., Nachbur, U., Huang, D. C. S., Bouillet, P., Thomas, H. E., Borner, C., Silke, J., Strasser, A., Kaufmann, T. <strong>XIAP discriminates between type I and type II FAS-induced apoptosis.</strong> Nature 460: 1035-1039, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19626005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19626005</a>] [<a href="https://doi.org/10.1038/nature08229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19626005">Jost et al. (2009)</a>, distinct cell types differ in the mechanisms by which the 'death receptor' FAS (<a href="/entry/134637">134637</a>) triggers their apoptosis. In type I cells, such as lymphocytes, activation of effector caspases by FAS-induced activation of caspase-8 (<a href="/entry/601763">601763</a>) suffices for cell killing; in type II cells, including hepatocytes and pancreatic beta-cells, caspase cascade amplification through caspase-8-mediated activation of the proapoptotic BID (<a href="/entry/601197">601197</a>) is essential. <a href="#12" class="mim-tip-reference" title="Jost, P. J., Grabow, S., Gray, D., McKenzie, M. D., Nachbur, U., Huang, D. C. S., Bouillet, P., Thomas, H. E., Borner, C., Silke, J., Strasser, A., Kaufmann, T. <strong>XIAP discriminates between type I and type II FAS-induced apoptosis.</strong> Nature 460: 1035-1039, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19626005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19626005</a>] [<a href="https://doi.org/10.1038/nature08229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19626005">Jost et al. (2009)</a> demonstrated that loss of XIAP function by gene targeting or treatment with a DIABLO (<a href="/entry/605219">605219</a>) mimetic drug in mice rendered hepatocytes and beta-cells independent of BID for FAS-induced apoptosis. <a href="#12" class="mim-tip-reference" title="Jost, P. J., Grabow, S., Gray, D., McKenzie, M. D., Nachbur, U., Huang, D. C. S., Bouillet, P., Thomas, H. E., Borner, C., Silke, J., Strasser, A., Kaufmann, T. <strong>XIAP discriminates between type I and type II FAS-induced apoptosis.</strong> Nature 460: 1035-1039, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19626005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19626005</a>] [<a href="https://doi.org/10.1038/nature08229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19626005">Jost et al. (2009)</a> concluded that their results showed that XIAP is the critical discriminator between type I and type II apoptosis signaling and suggested that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19626005" 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 RT-PCR analysis, <a href="#11" class="mim-tip-reference" title="Jeon, S. Y., Lee, H.-J., Na, K.-H., Cha, D.-H., Kim, J. K., Park, J.-W., Yoon, T. K., Kim, G. J. <strong>Hypoxia-induced downregulation of XIAP in trophoblasts mediates apoptosis via interaction with IMUP-2: implications for placental development during pre-eclampsia.</strong> J. Cell. Biochem. 114: 89-98, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22886722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22886722</a>] [<a href="https://doi.org/10.1002/jcb.24304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22886722">Jeon et al. (2013)</a> showed that XIAP was strongly expressed in normal placenta, but that its expression was decreased in second and third trimester-onset preeclamptic placenta. Further analysis revealed that decreased expression of XIAP under hypoxic conditions induced apoptosis in HTR-8 SV/neo human trophoblasts, with involvement of HIF1A (<a href="/entry/603348">603348</a>), a key transcription factor in hypoxia-induced gene regulation. Hypoxia induced translocation of XIAP from cytoplasm to nucleus in HTR-8/SVneo trophoblasts, which was mediated by HIF1A. In nucleus, XIAP interacted and colocalized with IMUP2 (C19ORF33; <a href="/entry/619711">619711</a>) and increased IMUP2 expression, thereby inducing apoptosis in trophoblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22886722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Crystal Structure</em></strong></p><p>
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To reveal the mechanisms of effector caspase inhibition by inhibitors of apoptosis, and to provide a basis for improved drug design, <a href="#1" class="mim-tip-reference" title="Chai, J., Shiozaki, E., Srinivasula, S. M., Wu, Q., Datta, P., Alnemri, E. S., Shi, Y. <strong>Structural basis of caspase-7 inhibition by XIAP.</strong> Cell 104: 769-780, 2001. Note: Erratum: Cell 107: 409 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11257230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11257230</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00272-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11257230">Chai et al. (2001)</a> determined the crystal structure of an active caspase-7 bound to a potent inhibitory domain of XIAP (residues 124 to 240). Similarly, <a href="#10" class="mim-tip-reference" title="Huang, Y., Park, Y. C., Rich, R. L., Segal, D., Myszka, D. G., Wu, H. <strong>Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain.</strong> Cell 104: 781-790, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11257231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11257231</a>]" pmid="11257231">Huang et al. (2001)</a> reported the crystal structure of the complex between human caspase-7 and the BIR2 domain and the proceeding linker of XIAP. <a href="#20" class="mim-tip-reference" title="Riedl, S. J., Renatus, M., Schwarzenbacher, R., Zhou, Q., Sun, C., Fesik, S. W., Liddington, R. C., Salvesen, G. S. <strong>Structural basis for the inhibition of caspase-3 by XIAP.</strong> Cell 104: 791-800, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11257232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11257232</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00274-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11257232">Riedl et al. (2001)</a> reported the crystal structure of the BIR2 domain of XIAP in complex with caspase-3. They determined that the mechanism of inhibition is due to a steric blockade prohibitive of substrate binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11257232+11257231+11257230" 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="Shiozaki, E. N., Chai, J., Rigotti, D. J., Riedl, S. J., Li, P., Srinivasula, S. M., Alnemri, E. S., Fairman, R., Shi, Y. <strong>Mechanism of XIAP-mediated inhibition of caspase-9.</strong> Molec. Cell 11: 519-527, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12620238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12620238</a>] [<a href="https://doi.org/10.1016/s1097-2765(03)00054-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12620238">Shiozaki et al. (2003)</a> reported the crystal structure of caspase-9 in an inhibitory complex with the BIR3 domain of XIAP at 2.4-angstrom resolution. The structure revealed that the BIR3 domain forms a heterodimer with a caspase-9 monomer. The surface of caspase-9 that interacts with BIR3 also mediates its homodimerization. Monomeric caspase-9 is catalytically inactive due to the absence of a supporting sequence element that could be provided by homodimerization. The authors concluded that XIAP sequesters caspase-9 in a monomeric state, which serves to prevent catalytic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12620238" 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>Solution Structure</em></strong></p><p>
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To understand the structural basis of molecular recognition between SMAC and the IAPs, <a href="#16" class="mim-tip-reference" title="Liu, Z., Sun, C., Olejniczak, E. T., Meadows, R. P., Betz, S. F., Oost, T., Herrmann, J., Wu, J. C., Fesik, S. W. <strong>Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain.</strong> Nature 408: 1004-1008, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11140637/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11140637</a>] [<a href="https://doi.org/10.1038/35050006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11140637">Liu et al. (2000)</a> determined the solution structure of the BIR3 domain of XIAP complexed with a functionally active 9-residue peptide derived from the N terminus of SMAC. <a href="#28" class="mim-tip-reference" title="Wu, G., Chai, J., Suber, T. L., Wu, J.-W., Du, C., Wang, X., Shi, Y. <strong>Structural basis of IAP recognition by Smac/DIABLO.</strong> Nature 408: 1008-1012, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11140638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11140638</a>] [<a href="https://doi.org/10.1038/35050012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11140638">Wu et al. (2000)</a> performed the same experiment. They found that the N-terminal 4 residues (ala-val-pro-ile) in SMAC/DIABLO recognize a surface groove on BIR3, with the first residue ala binding a hydrophobic pocket and making 5 hydrogen bonds to neighboring residues on BIR3. These observations provided a structural explanation for the roles of the SMAC N terminus as well as for the conserved N-terminal sequences in the Drosophila proteins Hid/Grim/Reaper. In conjunction with other observations, <a href="#28" class="mim-tip-reference" title="Wu, G., Chai, J., Suber, T. L., Wu, J.-W., Du, C., Wang, X., Shi, Y. <strong>Structural basis of IAP recognition by Smac/DIABLO.</strong> Nature 408: 1008-1012, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11140638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11140638</a>] [<a href="https://doi.org/10.1038/35050012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11140638">Wu et al. (2000)</a> concluded that their results reveal how SMAC may relieve IAP inhibition of caspase-9 activity. In addition to explaining a number of biologic observations, both <a href="#16" class="mim-tip-reference" title="Liu, Z., Sun, C., Olejniczak, E. T., Meadows, R. P., Betz, S. F., Oost, T., Herrmann, J., Wu, J. C., Fesik, S. W. <strong>Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain.</strong> Nature 408: 1004-1008, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11140637/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11140637</a>] [<a href="https://doi.org/10.1038/35050006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11140637">Liu et al. (2000)</a> and <a href="#28" class="mim-tip-reference" title="Wu, G., Chai, J., Suber, T. L., Wu, J.-W., Du, C., Wang, X., Shi, Y. <strong>Structural basis of IAP recognition by Smac/DIABLO.</strong> Nature 408: 1008-1012, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11140638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11140638</a>] [<a href="https://doi.org/10.1038/35050012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11140638">Wu et al. (2000)</a> suggested that their structural analyses identified potential targets for drug screening that may be used for the treatment of cancers that overexpress IAPs. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11140637+11140638" 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="#21" class="mim-tip-reference" title="Rigaud, S., Fondaneche, M.-C., Lambert, N., Pasquier, B., Mateo, V., Soulas, P., Galicier, L., Le Deist, F., Rieux-Laucat, F., Revy, P., Fischer, A., de Saint Basile, G., Latour, S. <strong>XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.</strong> Nature 444: 110-114, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17080092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17080092</a>] [<a href="https://doi.org/10.1038/nature05257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17080092">Rigaud et al. (2006)</a> determined that the XIAP gene comprises 6 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17080092" 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="#19" class="mim-tip-reference" title="Rajcan-Separovic, E., Liston, P., Lefebvre, C., Korneluk, R. G. <strong>Assignment of human inhibitor of apoptosis protein (IAP) genes xiap, hiap-1, and hiap-2 to chromosomes Xq25 and 11q22-q23 by fluorescence in situ hybridization.</strong> Genomics 37: 404-406, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8938457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8938457</a>] [<a href="https://doi.org/10.1006/geno.1996.0579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8938457">Rajcan-Separovic et al. (1996)</a> used fluorescence in situ hybridization (FISH) to map the XIAP gene to chromosome Xq25. By FISH, <a href="#8" class="mim-tip-reference" title="Farahani, R., Fong, W. G., Korneluk, R. G., MacKenzie, A. E. <strong>Genomic organization and primary characterization of miap-3: the murine homologue of human X-linked IAP.</strong> Genomics 42: 514-518, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9205126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9205126</a>] [<a href="https://doi.org/10.1006/geno.1997.4742" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9205126">Farahani et al. (1997)</a> mapped the mouse miap3 gene to the X chromosome, region A3-A5. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8938457+9205126" 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 affected males from 3 families with X-linked lymphoproliferative syndrome-2 (XLP2; <a href="/entry/300635">300635</a>), <a href="#21" class="mim-tip-reference" title="Rigaud, S., Fondaneche, M.-C., Lambert, N., Pasquier, B., Mateo, V., Soulas, P., Galicier, L., Le Deist, F., Rieux-Laucat, F., Revy, P., Fischer, A., de Saint Basile, G., Latour, S. <strong>XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.</strong> Nature 444: 110-114, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17080092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17080092</a>] [<a href="https://doi.org/10.1038/nature05257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17080092">Rigaud et al. (2006)</a> identified hemizygous frameshift, nonsense, and deletion mutations in the XIAP gene (<a href="#0001">300079.0001</a>-<a href="#0003">300079.0003</a>). Despite similarities in clinical features, patients with XIAP deficiency showed different cellular manifestations than did patients with SAP deficiency (XLP1; <a href="/entry/308240">308240</a>). <a href="#21" class="mim-tip-reference" title="Rigaud, S., Fondaneche, M.-C., Lambert, N., Pasquier, B., Mateo, V., Soulas, P., Galicier, L., Le Deist, F., Rieux-Laucat, F., Revy, P., Fischer, A., de Saint Basile, G., Latour, S. <strong>XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.</strong> Nature 444: 110-114, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17080092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17080092</a>] [<a href="https://doi.org/10.1038/nature05257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17080092">Rigaud et al. (2006)</a> showed that apoptosis of lymphocytes from XIAP-deficient patients is enhanced in response to various stimuli, including the T-cell antigen receptor (TCR)-CD3 complex (see <a href="/entry/186790">186790</a>), the death receptor CD95 (<a href="/entry/134637">134637</a>), and the TNF-associated apoptosis-inducing ligand receptor (TRAILR; see <a href="/entry/603613">603613</a>). <a href="#21" class="mim-tip-reference" title="Rigaud, S., Fondaneche, M.-C., Lambert, N., Pasquier, B., Mateo, V., Soulas, P., Galicier, L., Le Deist, F., Rieux-Laucat, F., Revy, P., Fischer, A., de Saint Basile, G., Latour, S. <strong>XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.</strong> Nature 444: 110-114, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17080092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17080092</a>] [<a href="https://doi.org/10.1038/nature05257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17080092">Rigaud et al. (2006)</a> also found that XIAP-deficient patients, like SAP-deficient patients, have low numbers of natural killer T lymphocytes (NKT cells), indicating that XIAP is required for the survival and/or differentiation of NKT cells. The observation that XIAP deficiency and SAP deficiency are both associated with a defect in NKT cells strengthened the hypothesis that NKT cells have a key role in the immune response to Epstein-Barr virus (EBV). Furthermore, by identifying an XLP immunodeficiency that is caused by mutations in XIAP, <a href="#21" class="mim-tip-reference" title="Rigaud, S., Fondaneche, M.-C., Lambert, N., Pasquier, B., Mateo, V., Soulas, P., Galicier, L., Le Deist, F., Rieux-Laucat, F., Revy, P., Fischer, A., de Saint Basile, G., Latour, S. <strong>XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.</strong> Nature 444: 110-114, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17080092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17080092</a>] [<a href="https://doi.org/10.1038/nature05257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17080092">Rigaud et al. (2006)</a> showed that XIAP is a potent regulator of lymphocyte homeostasis in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17080092" 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="Worthey, E. A., Mayer, A. N., Syverson, G. D., Helbling, D., Bonacci, B. B., Decker, B., Serpe, J. M., Dasu, T., Tschannen, M. R., Veith, R. L., Basehore, M. J., Broeckel, U., and 10 others. <strong>Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease.</strong> Genet. Med. 13: 255-262, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21173700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21173700</a>] [<a href="https://doi.org/10.1097/GIM.0b013e3182088158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21173700">Worthey et al. (2011)</a> identified a missense mutation of a highly conserved cysteine in the XIAP gene in a child with XLP2 manifesting as intractable inflammatory bowel disease (<a href="#0004">300079.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21173700" 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 9 Japanese male patients from 6 unrelated Japanese families with XLP2, <a href="#29" class="mim-tip-reference" title="Yang, X., Kanegane, H., Nishida, N., Imamura, T., Hamamoto, K., Miyashita, R., Imai, K., Nonoyama, S., Sanayama, K., Yamaide, A., Kato, F., Nagai, K., Ishii, E., van Zelm, M. C., Latour, S., Zhao, X.-D., Miyawaki, T. <strong>Clinical and genetic characteristics of XIAP deficiency in Japan.</strong> J. Clin. Immun. 32: 411-420, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22228567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22228567</a>] [<a href="https://doi.org/10.1007/s10875-011-9638-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22228567">Yang et al. (2012)</a> identified 6 different truncating mutations in the XIAP gene (see, e.g., <a href="#0005">300079.0005</a>-<a href="#0007">300079.0007</a>). The mutations were found by direct screening of the XIAP gene after exclusion of mutations in the SH2D1A gene (<a href="/entry/300490">300490</a>). The mothers of patients from families 1 through 5 were heterozygous carriers of the mutations, whereas the mother of 2 sibs (family 6) did not carry the mutation in peripheral blood, suggesting germline mosaicism. Flow cytometric analysis of patient lymphocytes showed decreased expression in 7 of 8 patients; low-normal expression was found in a patient (patient 4) with an in-frame deletion mutation (E349del; <a href="#0005">300079.0005</a>) who had a milder phenotype with only hypogammaglobulinemia and recurrent infections. The expression pattern of XIAP in carrier mother cells was variably reduced or showed a bimodal pattern. Western blot analysis, performed on 3 patients, showed decreased XIAP levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22228567" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 6 affected males from a large Caucasian family with XLP2, <a href="#7" class="mim-tip-reference" title="Dziadzio, M., Ammann, S., Canning, C., Boyle, F., Hassan, A., Cale, C., Elawad, M., Fiil, B. K., Gyrd-Hansen, M., Salzer, U., Speckmann, C., Grimbacher, B. <strong>Symptomatic male and female carriers in a large Caucasian kindred with XIAP deficiency.</strong> J. Clin. Immun. 35: 439-444, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25943627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25943627</a>] [<a href="https://doi.org/10.1007/s10875-015-0166-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25943627">Dziadzio et al. (2015)</a> identified a truncating mutation in the XIAP gene (<a href="#0008">300079.0008</a>). There were 7 female carriers, 6 of whom were symptomatic to varying degrees. Flow cytometric analysis of peripheral cells from 1 of the affected males showed absence of the XIAP protein and a severely abrogated response of monocytes to NOD2 (<a href="/entry/605956">605956</a>), with decreased TNF-alpha (<a href="/entry/191160">191160</a>) production. Flow cytometric analysis of lymphocyte subsets and monocytes from 3 female carriers showed revealed preferential expression of XIAP wildtype protein and normal NOD2 function. However, the most severely affected female carrier (patient IV.9) with IBD and erythema nodosum (EN) had random X-inactivation, resulting in expression of the mutated XIAP protein in her monocytes and impaired NOD2 responses in vitro. These findings indicated that the pattern of X-inactivation can influence the phenotype in female carriers. The findings also indicated that impaired NOD2 signaling is a driving pathophysiologic mechanism of the disorder. In addition, the truncated mutation also resulted in increased activation-induced cell death (AICD) of patient-derived T-cell blasts in vitro, suggesting that the mutation also affected the antiapoptotic properties of XIAP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25943627" 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="#9" class="mim-tip-reference" title="Harlin, H., Reffey, S. B., Duckett, C. S., Lindsten, T., Thompson, C. B. <strong>Characterization of XIAP-deficient mice.</strong> Molec. Cell. Biol. 21: 3604-3608, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11313486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11313486</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11313486[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/MCB.21.10.3604-3608.2001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11313486">Harlin et al. (2001)</a> generated mice deficient in Xiap through homologous gene targeting. The Xiap -/- mice were viable, histopathologically normal, and lacked defects in caspase-dependent or -independent apoptosis. However, the levels of Ciap1 and Ciap2 were increased, suggesting the existence of a compensatory mechanism in the absence of XIAP expression that may be provided by these molecules. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11313486" 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 review, <a href="#14" class="mim-tip-reference" title="Latour, S., Aguilar, C. <strong>XIAP deficiency syndrome in humans.</strong> Semin. Cell Dev. Biol. 39: 115-123, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25666262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25666262</a>] [<a href="https://doi.org/10.1016/j.semcdb.2015.01.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25666262">Latour and Aguilar (2015)</a> noted that studies have shown that certain strains of Xiap-deficient mice have compromised immunity leading to decreased survival when infected with certain pathogens, including intracellular bacteria and viruses. These infections are associated with splenomegaly and compromised innate immunity with altered cytokine production. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25666262" 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 bone marrow-derived macrophages (BMDMs) from Xiap-deficient mice, <a href="#2" class="mim-tip-reference" title="Chiang, S. C. C., Owsley, E., Panchal, N., Chaturvedi, V., Terrell, C. E., Jordan, M. B., Mehta, P. A., Davies, S. M., Akeno, N., Booth, C., Marsh, R. A. <strong>Quercetin ameliorates XIAP deficiency-associated hyperinflammation.</strong> Blood 140: 706-715, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35687753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35687753</a>] [<a href="https://doi.org/10.1182/blood.2021014335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35687753">Chiang et al. (2022)</a> demonstrated that Il1-beta (<a href="/entry/147720">147720</a>) was produced in response to stimulation with Tnf-alpha (<a href="/entry/191160">191160</a>) or Tlr (see <a href="/entry/601194">601194</a>) agonists without the requirement of a second activation signal. This second activation signal was required by wildtype BMDMs. Furthermore, in BMDMs derived from mice that were deficient in both Xiap and Nrpl3 (<a href="/entry/600928">600928</a>), IL1-beta production was reduced compared to BMDMs from Xiap-deficient mice. <a href="#2" class="mim-tip-reference" title="Chiang, S. C. C., Owsley, E., Panchal, N., Chaturvedi, V., Terrell, C. E., Jordan, M. B., Mehta, P. A., Davies, S. M., Akeno, N., Booth, C., Marsh, R. A. <strong>Quercetin ameliorates XIAP deficiency-associated hyperinflammation.</strong> Blood 140: 706-715, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35687753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35687753</a>] [<a href="https://doi.org/10.1182/blood.2021014335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35687753">Chiang et al. (2022)</a> concluded that the NLRP3 inflammasome complex plays a role in the hyperinflammation in X-linked lymphoproliferative syndrome. When the Xiap-deficient BMDMs were treated with MCC950 (an NLRP3 inhibitor), chloroquine (an inhibitor of lysosome acidification) or quercetin (an antioxidant), Il1-beta overproduction was abrogated. <a href="#2" class="mim-tip-reference" title="Chiang, S. C. C., Owsley, E., Panchal, N., Chaturvedi, V., Terrell, C. E., Jordan, M. B., Mehta, P. A., Davies, S. M., Akeno, N., Booth, C., Marsh, R. A. <strong>Quercetin ameliorates XIAP deficiency-associated hyperinflammation.</strong> Blood 140: 706-715, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35687753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35687753</a>] [<a href="https://doi.org/10.1182/blood.2021014335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35687753">Chiang et al. (2022)</a> showed that treated Xiap-deficient mice with quercetin had reduced cytokine production after LPS exposure compared to untreated Xiap-deficient mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35687753" 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=300079[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 2</strong>
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<p>In affected males from a family (family 1) with X-linked lymphoproliferative syndrome (XLP2; <a href="/entry/300635">300635</a>), <a href="#21" class="mim-tip-reference" title="Rigaud, S., Fondaneche, M.-C., Lambert, N., Pasquier, B., Mateo, V., Soulas, P., Galicier, L., Le Deist, F., Rieux-Laucat, F., Revy, P., Fischer, A., de Saint Basile, G., Latour, S. <strong>XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.</strong> Nature 444: 110-114, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17080092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17080092</a>] [<a href="https://doi.org/10.1038/nature05257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17080092">Rigaud et al. (2006)</a> detected hemizygosity for deletion of the cytidine at nucleotide position 291 of the XIAP gene (c.291delC), resulting in a frameshift leading to a stop codon at position 387 (G99K/X129). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17080092" 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 affected males from a family (family 3) with X-linked lymphoproliferative syndrome (XLP2; <a href="/entry/300635">300635</a>), <a href="#21" class="mim-tip-reference" title="Rigaud, S., Fondaneche, M.-C., Lambert, N., Pasquier, B., Mateo, V., Soulas, P., Galicier, L., Le Deist, F., Rieux-Laucat, F., Revy, P., Fischer, A., de Saint Basile, G., Latour, S. <strong>XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.</strong> Nature 444: 110-114, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17080092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17080092</a>] [<a href="https://doi.org/10.1038/nature05257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17080092">Rigaud et al. (2006)</a> identified a hemizygous c.352G-T transversion in the XIAP gene, resulting in a glu118-to-ter (E118X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17080092" 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 affected males from a family (family 2) with X-linked lymphoproliferative syndrome (XLP2; <a href="/entry/300635">300635</a>), <a href="#21" class="mim-tip-reference" title="Rigaud, S., Fondaneche, M.-C., Lambert, N., Pasquier, B., Mateo, V., Soulas, P., Galicier, L., Le Deist, F., Rieux-Laucat, F., Revy, P., Fischer, A., de Saint Basile, G., Latour, S. <strong>XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.</strong> Nature 444: 110-114, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17080092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17080092</a>] [<a href="https://doi.org/10.1038/nature05257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17080092">Rigaud et al. (2006)</a> detected a hemizygous deletion of 2,606 nucleotides encompassing exon 2 of the XIAP gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17080092" 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 boy with X-linked lymphoproliferative syndrome (XLP2; <a href="/entry/300635">300635</a>) manifesting as intractable inflammatory bowel disease, <a href="#27" class="mim-tip-reference" title="Worthey, E. A., Mayer, A. N., Syverson, G. D., Helbling, D., Bonacci, B. B., Decker, B., Serpe, J. M., Dasu, T., Tschannen, M. R., Veith, R. L., Basehore, M. J., Broeckel, U., and 10 others. <strong>Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease.</strong> Genet. Med. 13: 255-262, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21173700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21173700</a>] [<a href="https://doi.org/10.1097/GIM.0b013e3182088158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21173700">Worthey et al. (2011)</a> undertook whole-exome sequencing and identified a hemizygous G-to-A substitution at a highly conserved position in the XIAP gene, resulting in a hemizygous cys-to-tyr amino acid substitution at codon 203 (C203Y). This mutation was not found in more than 2,000 human control sequences or in orthologous genes from other species down to Drosophila. Confirmation of the variant in the child was carried out by Sanger sequencing, and studies on the mother confirmed the mutation and showed maternal skewed X-chromosome inactivation in natural killer, B, and T helper cell types. Functional assays demonstrated an increased susceptibility to activation-induced cell death and defective responsiveness to NOD2 (<a href="/entry/605956">605956</a>) ligands, consistent with loss of normal XIAP function in apoptosis and NOD2 signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21173700" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs199683465 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199683465;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs199683465?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199683465" 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=rs199683465" 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 15-year-old Japanese boy (patient 4) with X-linked lymphoproliferative syndrome (XLP2; <a href="/entry/300635">300635</a>) manifesting only as hypogammaglobulinemia with recurrent infections, <a href="#29" class="mim-tip-reference" title="Yang, X., Kanegane, H., Nishida, N., Imamura, T., Hamamoto, K., Miyashita, R., Imai, K., Nonoyama, S., Sanayama, K., Yamaide, A., Kato, F., Nagai, K., Ishii, E., van Zelm, M. C., Latour, S., Zhao, X.-D., Miyawaki, T. <strong>Clinical and genetic characteristics of XIAP deficiency in Japan.</strong> J. Clin. Immun. 32: 411-420, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22228567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22228567</a>] [<a href="https://doi.org/10.1007/s10875-011-9638-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22228567">Yang et al. (2012)</a> identified a hemizygous in-frame 3-bp deletion (c.1045_1047delGAG) in exon 3 of the XIAP gene, resulting in a deletion of residue glu349 (E349del). Flow cytometric analysis of patient lymphocytes detected normal levels of XIAP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22228567" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Nishida, N., Yang, X., Takasaki, I., Imai, K., Kato, K., Inoue, Y., Imamura, T., Miyashita, R., Kato, F., Yamaide, A., Mori, M., Saito, S., Hara, J., Adachi, Y., Miyawaki, T., Kanegane, H. <strong>Dysgammaglobulinemia associated with glu349del, a hypomorphic XIAP mutation.</strong> J. Invest. Allergol. Clin. Immun. 25: 205-213, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26182687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26182687</a>]" pmid="26182687">Nishida et al. (2015)</a> identified 3 additional Japanese boys (patients 4, 9, and 10) with XLP2 due to a hemizygous E349del variant. The disorder manifested as hypogammaglobulinemia only, although 1 of the patients developed aplastic anemia requiring hematopoietic stem cell transplantation. The patients had normal XIAP protein expression, but decreased numbers of CD19+ switched memory B cells. Patient cells did not showed increased activation-induced cell death (AICD) of T lymphocytes compared to controls. Microarray analysis indicated that the gene expression patterns were different in patients with the E349del mutation compared to patients with other mutations in the XIAP gene. Patients with E349del had 10-fold lower expression of a number of genes, including those involved in B cell development and Ig levels. <a href="#18" class="mim-tip-reference" title="Nishida, N., Yang, X., Takasaki, I., Imai, K., Kato, K., Inoue, Y., Imamura, T., Miyashita, R., Kato, F., Yamaide, A., Mori, M., Saito, S., Hara, J., Adachi, Y., Miyawaki, T., Kanegane, H. <strong>Dysgammaglobulinemia associated with glu349del, a hypomorphic XIAP mutation.</strong> J. Invest. Allergol. Clin. Immun. 25: 205-213, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26182687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26182687</a>]" pmid="26182687">Nishida et al. (2015)</a> stated that the variant occurred in exon 4 of the XIAP gene and that it was a polymorphism in the Japanese population. Among 170 healthy Japanese individuals, 2 were heterozygous and 4 homozygous for the variant. <a href="#18" class="mim-tip-reference" title="Nishida, N., Yang, X., Takasaki, I., Imai, K., Kato, K., Inoue, Y., Imamura, T., Miyashita, R., Kato, F., Yamaide, A., Mori, M., Saito, S., Hara, J., Adachi, Y., Miyawaki, T., Kanegane, H. <strong>Dysgammaglobulinemia associated with glu349del, a hypomorphic XIAP mutation.</strong> J. Invest. Allergol. Clin. Immun. 25: 205-213, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26182687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26182687</a>]" pmid="26182687">Nishida et al. (2015)</a> concluded that although the E349del variant is a SNP, it could be associated with hypo/dysgammaglobulinemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26182687" 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">rs1556406033 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1556406033;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=rs1556406033" 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=rs1556406033" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 Japanese brothers (patient 6.1 and 6.2) with X-linked lymphoproliferative syndrome (XLP2; <a href="/entry/300635">300635</a>), <a href="#29" class="mim-tip-reference" title="Yang, X., Kanegane, H., Nishida, N., Imamura, T., Hamamoto, K., Miyashita, R., Imai, K., Nonoyama, S., Sanayama, K., Yamaide, A., Kato, F., Nagai, K., Ishii, E., van Zelm, M. C., Latour, S., Zhao, X.-D., Miyawaki, T. <strong>Clinical and genetic characteristics of XIAP deficiency in Japan.</strong> J. Clin. Immun. 32: 411-420, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22228567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22228567</a>] [<a href="https://doi.org/10.1007/s10875-011-9638-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22228567">Yang et al. (2012)</a> identified a hemizygous 2-bp deletion (c.1021_1022delAA) in exon 3, resulting in a frameshift and premature termination (Asn341TyrfsTer7). The mutation was not detected in the mother's lymphocytes, suggesting germline mosaicism. Flow cytometric and Western blot analysis of patient lymphocytes showed decreased levels of XIAP, consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22228567" 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">rs1556404673 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1556404673;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=rs1556404673" 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=rs1556404673" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 Japanese brothers (patients 3.1 and 3.2) with X-linked lymphoproliferative syndrome (XLP2; <a href="/entry/300635">300635</a>), <a href="#29" class="mim-tip-reference" title="Yang, X., Kanegane, H., Nishida, N., Imamura, T., Hamamoto, K., Miyashita, R., Imai, K., Nonoyama, S., Sanayama, K., Yamaide, A., Kato, F., Nagai, K., Ishii, E., van Zelm, M. C., Latour, S., Zhao, X.-D., Miyawaki, T. <strong>Clinical and genetic characteristics of XIAP deficiency in Japan.</strong> J. Clin. Immun. 32: 411-420, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22228567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22228567</a>] [<a href="https://doi.org/10.1007/s10875-011-9638-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22228567">Yang et al. (2012)</a> identified a hemizygous 1-bp deletion (c.650delG) in exon 1 of the XIAP gene, resulting in a frameshift and premature termination (Trp217CysfsTer27). Interestingly, 1 patient had a severe disorder with onset at age 2 months and recurrent EBV-associated HLH, whereas the other was asymptomatic at age 17 years. Flow cytometric and Western blot analysis of patient lymphocytes showed decreased levels of XIAP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22228567" 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">rs1556404697 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1556404697;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=rs1556404697" 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=rs1556404697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 6 affected males from a large Caucasian family with X-linked lymphoproliferative syndrome (XLP2; <a href="/entry/300635">300635</a>), <a href="#7" class="mim-tip-reference" title="Dziadzio, M., Ammann, S., Canning, C., Boyle, F., Hassan, A., Cale, C., Elawad, M., Fiil, B. K., Gyrd-Hansen, M., Salzer, U., Speckmann, C., Grimbacher, B. <strong>Symptomatic male and female carriers in a large Caucasian kindred with XIAP deficiency.</strong> J. Clin. Immun. 35: 439-444, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25943627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25943627</a>] [<a href="https://doi.org/10.1007/s10875-015-0166-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25943627">Dziadzio et al. (2015)</a> identified a 1-bp duplication (c.672dupT) in exon 2 of the XIAP gene, resulting in a frameshift and premature termination (Pro225SerfsTer2) in the BIR2 domain. Four of 5 affected males had severe inflammatory bowel disease (IBD), and 6 of 7 carrier females had chronic erythema nodosum (EN) and variable bowel symptoms. One female carrier was asymptomatic. Flow cytometric analysis of peripheral blood cells from 1 of the affected males showed absence of the XIAP protein and a severely abrogated response of monocytes to NOD2. Flow cytometric analysis of lymphocyte subsets and monocytes from 3 female carriers showed preferential expression of XIAP wildtype protein and normal NOD2 function. However, the most severely affected female carrier (patient IV.9) with IBD and EN had expression of mutated XIAP protein in her monocytes, leading to impaired NOD2 responses in vitro. These observations indicated that impaired NOD2 signaling is a driving pathophysiologic mechanism of the disorder. In addition, the truncated mutation also resulted in increased activation-induced cell death (AICD) of patient-derived T-cell blasts in vitro, suggesting that the mutation also affects the antiapoptotic properties of XIAP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25943627" 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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Cell 104: 769-780, 2001. Note: Erratum: Cell 107: 409 only, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11257230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11257230</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11257230" 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/10.1006/geno.1996.0579" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M203312200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s1097-2765(03)00054-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/35065125" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/35050012" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10875-011-9638-z" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10797013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10797013</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10797013" 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.288.5467.874" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 03/30/2023
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Bao Lige - updated : 01/12/2022<br>Cassandra L. Kniffin - updated : 11/28/2017<br>Ada Hamosh - updated : 9/28/2012<br>Ada Hamosh - updated : 9/15/2009<br>Patricia A. Hartz - updated : 8/13/2009<br>Patricia A. Hartz - updated : 8/6/2007<br>Ada Hamosh - updated : 1/10/2007<br>Patricia A. Hartz - updated : 4/10/2006<br>Patricia A. Hartz - updated : 8/17/2004<br>Stylianos E. Antonarakis - updated : 4/21/2003<br>Patricia A. Hartz - updated : 11/8/2002<br>Paul J. Converse - updated : 4/23/2002<br>Paul J. Converse - updated : 11/14/2001<br>Stylianos E. Antonarakis - updated : 4/16/2001<br>Ada Hamosh - updated : 5/4/2000<br>Rebekah S. Rasooly - updated : 2/22/1999<br>Victor A. McKusick - updated : 9/9/1997<br>Jennifer P. Macke - updated : 7/29/1997
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Jennifer P. Macke : 3/24/1997
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mgross : 01/18/2022<br>mgross : 01/12/2022<br>alopez : 12/05/2017<br>ckniffin : 11/28/2017<br>carol : 09/14/2016<br>terry : 04/04/2013<br>alopez : 10/2/2012<br>terry : 9/28/2012<br>wwang : 1/5/2011<br>alopez : 9/15/2009<br>terry : 9/15/2009<br>mgross : 8/13/2009<br>terry : 8/13/2009<br>mgross : 8/9/2007<br>terry : 8/6/2007<br>alopez : 1/16/2007<br>terry : 1/10/2007<br>terry : 1/10/2007<br>mgross : 4/12/2006<br>terry : 4/10/2006<br>mgross : 8/26/2004<br>terry : 8/17/2004<br>carol : 11/12/2003<br>carol : 7/24/2003<br>mgross : 4/21/2003<br>mgross : 11/8/2002<br>mgross : 4/23/2002<br>mgross : 2/18/2002<br>alopez : 11/14/2001<br>alopez : 11/14/2001<br>mgross : 4/16/2001<br>mgross : 4/16/2001<br>alopez : 2/28/2001<br>carol : 12/23/2000<br>mgross : 9/15/2000<br>alopez : 5/4/2000<br>alopez : 2/22/1999<br>alopez : 2/22/1999<br>alopez : 12/22/1998<br>carol : 9/22/1998<br>alopez : 11/24/1997<br>jenny : 9/18/1997<br>terry : 9/9/1997<br>alopez : 9/8/1997<br>alopez : 9/5/1997<br>terry : 7/29/1997<br>alopez : 7/1/1997<br>alopez : 4/2/1997<br>alopez : 3/31/1997<br>alopez : 3/25/1997<br>alopez : 3/24/1997
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<span class="mim-font">
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<strong>*</strong> 300079
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</h3>
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<h3>
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INHIBITOR OF APOPTOSIS, X-LINKED; XIAP
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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BACULOVIRAL IAP REPEAT-CONTAINING PROTEIN 4; BIRC4<br />
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APOPTOSIS INHIBITOR 3; API3<br />
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IAP-LIKE PROTEIN; ILP<br />
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MAMMALIAN IAP HOMOLOG A; MIHA
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: XIAP</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1162830004;
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<strong>
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Cytogenetic location: Xq25
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Genomic coordinates <span class="small">(GRCh38)</span> : X:123,859,708-123,913,972 </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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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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Xq25
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Lymphoproliferative syndrome, X-linked, 2
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<span class="mim-font">
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300635
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X-linked recessive
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<span class="mim-font">
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<strong>Description</strong>
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<p>The XIAP gene belongs to the 'inhibitor of apoptosis protein' (IAP) gene family, which also includes HIAP1 (601721), and HIAP2 (601712). XIAP has a capacity to block apoptosis by directly inhibiting certain caspases. In addition to its antiapoptotic function, XIAP is involved in a variety of signaling pathways and/or cellular responses through ubiquitylation or as a signal transducer for the Nod-like receptors NOD1 (605980) and NOD2 (605956), which play a role in innate immunity (review by Latour and Aguilar, 2015). </p>
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<strong>Cloning and Expression</strong>
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<p>Duckett et al. (1996) cloned the XIAP gene, which they referred to as hILP, for 'human IAP-like protein.' They reported that the gene encodes a 497-amino acid polypeptide with a predicted mass of 57 kD. They further noted that the sequence contains BIRs (baculovirus IAP repeats) and RING finger domains. Duckett et al. (1996) considered data gleaned from EST database analysis to be evidence that hILP is one of several human genes related to IAP. Duckett et al. (1996) expressed hILP in mammalian cell lines and found that it was able to block virally induced apoptosis. </p><p>Uren et al. (1996) reported that XIAP, which they called MIHA, shares 43% protein sequence identity with HIAP1 and HIAP2. Uren et al. (1996) determined that expression of XIAP in mammalian cells significantly reduced ICE (147678)-mediated apoptosis. </p><p>Liston et al. (1996) found that XIAP inhibited serum deprivation-induced apoptosis and apoptosis triggered by treatment with menadione, a potent inducer of free radicals. Northern blot analysis revealed XIAP expression as a 9-kb mRNA in all fetal and adult tissues tested except peripheral blood leukocytes. </p><p>Farahani et al. (1997) isolated cDNAs encoding miap3, the mouse XIAP homolog. The predicted 496-amino acid mouse protein is 94% identical to human XIAP. </p>
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<h4>
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<strong>Gene Function</strong>
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<span class="mim-text-font">
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<p>Deveraux et al. (1997) showed that human X-linked IAP directly inhibits at least 2 members of the caspase family of cell-death proteases, caspase-3 (CASP3; 600636) and caspase-7 (CASP7; 601761). As the caspases are highly conserved throughout the animal kingdom and are the principal effectors of apoptosis, these findings suggested how IAPs might inhibit cell death, providing evidence for a mechanism of action for these mammalian cell-death suppressors. </p><p>To determine why proteasome inhibitors prevent thymocyte death, Yang et al. (2000) examined whether proteasomes degrade antiapoptotic molecules in cells induced to undergo apoptosis. The HIAP2 and XIAP inhibitors of apoptosis were selectively lost in glucocorticoid- or etoposide-treated thymocytes in a proteasome-dependent manner before death. IAPs catalyzed their own ubiquitination in vitro, an activity requiring the RING domain. Overexpressed wildtype HIAP2, but not a RING domain mutant, was spontaneously ubiquitinated and degraded, and stably expressed XIAP lacking the RING domain was relatively resistant to apoptosis-induced degradation and, correspondingly, more effective at preventing apoptosis than wildtype XIAP. Yang et al. (2000) concluded that autoubiquitination and degradation of IAPs may be a key event in the apoptotic program. </p><p>XIAP interacts with caspase-9 (CASP9; 602234) and inhibits its activity, whereas SMAC (605219) relieves this inhibition through interaction with XIAP. Srinivasula et al. (2001) demonstrated that XIAP associates with the active caspase-9-APAF1 (602233) holoenzyme complex through binding to the amino terminus of the linker peptide on the small subunit of caspase-9, which becomes exposed after proteolytic processing of procaspase-9 at asp315. Supporting this observation, point mutations that abrogate the proteolytic processing but not the catalytic activity of caspase-9, or deletion of the linker peptide, prevented caspase-9 association with XIAP and its concomitant inhibition. Srinivasula et al. (2001) noted that the N-terminal 4 residues of caspase-9 linker peptide share significant homology with the N-terminal tetrapeptide in mature SMAC and in the Drosophila proteins Hid/Grim/Reaper, defining a conserved class of IAP-binding motifs. Consistent with this finding, binding of the caspase-9 linker peptide and SMAC to the BIR3 domain of XIAP is mutually exclusive, suggesting that SMAC potentiates caspase-9 activity by disrupting the interaction of the linker peptide of caspase-9 with BIR3. Srinivasula et al. (2001) concluded that their studies reveal a mechanism in which binding to the BIR3 domain of XIAP by 2 conserved peptides, one from SMAC and the other from caspase-9, has opposing effects on caspase activity and apoptosis. </p><p>IKKB (603258) is required for NFKB (see 164011) activation by TNFA (191160), whereas IKKA (600664) is dispensable. Using immune complex kinase assays to measure the effect of TNFA on the activities of IKK and JNK (e.g., 602897) in wildtype or RelA (164014)-, IKKA-, or IKKB-deficient mouse embryonic fibroblasts, Tang et al. (2001) found that JNK activation is transient in wildtype and Ikka -/- fibroblasts but sustained in RelA -/- and Ikkb -/- cells. In contrast, IKK activation was also transient but robust in Ikka -/- and wildtype fibroblasts but severely impaired in Ikkb -/- cells. Immunoblot analysis showed that Tnfa induced expression of XIAP in wildtype but not RelA -/- cells, indicating that XIAP is targeted by NFKB. Transient expression of XIAP in HeLa cells inhibited JNK activation by TNFA without affecting JNK expression levels. Expression of a dominant-negative JNKK2 (603014) mutant (K149M) or a constitutively active JNKK2-JNK1 (601158) fusion protein attenuated or enhanced, respectively, JNK activation and, in RelA -/- fibroblasts, cell death. Tang et al. (2001) concluded that IKK negatively modulates JNK activity, most likely through the induction of NFKB target genes encoding proteins such as XIAP, which interfere with TNFA-mediated, but not IL1 (147760)-mediated, JNK activation and apoptosis. </p><p>Sanna et al. (2002) determined that ILPIP (ALS2CR2; 607333) potentiates the antiapoptotic activity of XIAP by enhancing XIAP-mediated activation of JNK1 and other JNK family members, but not by modulating XIAP-mediated caspase inhibition. They also found that expression of a catalytically inactive TAK1 (MAP3K7; 602614) mutant blocked the XIAP/ILPIP activation of JNK1. In vivo coprecipitation experiments showed that both ILPIP and XIAP interact with TAK1 and TRAF6 (602355). Sanna et al. (2002) concluded that XIAP-mediated protection from apoptosis utilizes both a JNK1 activation pathway that involves ILPIP and a caspase inhibition pathway that is independent of ILPIP. </p><p>By targeted deletion, Cummins et al. (2004) disrupted the XIAP gene in human colon cancer cells. Deletion of the XIAP gene did not interfere with basal proliferation, but it enhanced sensitivity to exogenously added TRAIL (TNFSF10; 603598). TRAIL increased apoptosis in both XIAP knockout cells and wildtype cells, but the increase was markedly greater in knockout cells. The increased apoptosis in knockout cells correlated with higher levels of cleaved CASP3, but not of CASP7 or CASP9, compared with wildtype cells. Over a broad range of TRAIL doses, XIAP knockout cells exhibited reduced clonogenic survival and proliferation. Cummins et al. (2004) concluded that XIAP is a nonredundant modulator of TRAIL-mediated apoptosis. </p><p>Mufti et al. (2006) stated that XIAP interacts with and regulates the levels of COMMD1 (607238), a protein associated with a form of copper toxicosis in Bedlington terriers. They found that Xiap levels were greatly reduced by intracellular copper accumulation in affected Bedlington terriers, in other dogs with copper toxicosis disorders, in patients with Wilson disease (277900), and in human embryonic kidney (HEK293) cells cultured under high copper conditions. Elevated copper levels in HEK293 cells caused a profound, reversible conformational change in endogenous XIAP due to direct binding of copper to XIAP, which accelerated its degradation and significantly decreased its ability to inhibit CASP3, resulting in a lower apoptotic threshold that sensitized the cells to apoptosis. Mufti et al. (2006) hypothesized that regulation of cell death through XIAP may contribute to the pathophysiology of copper toxicosis disorders. </p><p>Dohi et al. (2007) stated that the antiapoptotic function of survivin (BIRC5; 603352) appears to rely on interactions with other molecules, including XIAP, and that mitochondrial and cytosolic survivin differ with respect to cell death inhibition. Using rat and human cells, Dohi et al. (2007) showed that protein kinase A (see 176911) phosphorylated survivin in the cytosol, but not in mitochondria. This phosphorylation event disrupted the binding interface between survivin and XIAP. Conversely, mitochondrial survivin or a nonphosphorylatable survivin mutant bound XIAP avidly, enhanced XIAP stability, synergistically inhibited apoptosis, and accelerated tumor growth in immunocompromised mice. Dohi et al. (2007) concluded that differential phosphorylation of survivin by PKA in subcellular microdomains regulates tumor cell apoptosis via its interaction with XIAP. </p><p>Kim et al. (2008) showed that ectopic expression of Xiap in bovine aortic endothelial cells blocked Tnf-induced apoptosis by a caspase-independent mechanism. Xiap-associated cell survival was the result of enhanced nitric oxide (NO) production. Xiap partially localized in caveolae, where it interacted via a motif within its BIR3 domain with caveolin-1 (CAV1; 601047), a regulator of NO production. Endothelial NO synthase (NOS3; 163729) binding to caveolin-1 was competitively inhibited by Xiap, suggesting that Xiap modulates NO production by releasing endothelial NO synthase from caveolin-1. In addition, Xiap-dependent NO controlled endothelial cell migration. </p><p>As summarized by Jost et al. (2009), distinct cell types differ in the mechanisms by which the 'death receptor' FAS (134637) triggers their apoptosis. In type I cells, such as lymphocytes, activation of effector caspases by FAS-induced activation of caspase-8 (601763) suffices for cell killing; in type II cells, including hepatocytes and pancreatic beta-cells, caspase cascade amplification through caspase-8-mediated activation of the proapoptotic BID (601197) is essential. Jost et al. (2009) demonstrated that loss of XIAP function by gene targeting or treatment with a DIABLO (605219) mimetic drug in mice rendered hepatocytes and beta-cells independent of BID for FAS-induced apoptosis. Jost et al. (2009) concluded that their results showed that XIAP is the critical discriminator between type I and type II apoptosis signaling and suggested that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions. </p><p>Using RT-PCR analysis, Jeon et al. (2013) showed that XIAP was strongly expressed in normal placenta, but that its expression was decreased in second and third trimester-onset preeclamptic placenta. Further analysis revealed that decreased expression of XIAP under hypoxic conditions induced apoptosis in HTR-8 SV/neo human trophoblasts, with involvement of HIF1A (603348), a key transcription factor in hypoxia-induced gene regulation. Hypoxia induced translocation of XIAP from cytoplasm to nucleus in HTR-8/SVneo trophoblasts, which was mediated by HIF1A. In nucleus, XIAP interacted and colocalized with IMUP2 (C19ORF33; 619711) and increased IMUP2 expression, thereby inducing apoptosis in trophoblasts. </p>
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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 class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
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To reveal the mechanisms of effector caspase inhibition by inhibitors of apoptosis, and to provide a basis for improved drug design, Chai et al. (2001) determined the crystal structure of an active caspase-7 bound to a potent inhibitory domain of XIAP (residues 124 to 240). Similarly, Huang et al. (2001) reported the crystal structure of the complex between human caspase-7 and the BIR2 domain and the proceeding linker of XIAP. Riedl et al. (2001) reported the crystal structure of the BIR2 domain of XIAP in complex with caspase-3. They determined that the mechanism of inhibition is due to a steric blockade prohibitive of substrate binding. </p><p>Shiozaki et al. (2003) reported the crystal structure of caspase-9 in an inhibitory complex with the BIR3 domain of XIAP at 2.4-angstrom resolution. The structure revealed that the BIR3 domain forms a heterodimer with a caspase-9 monomer. The surface of caspase-9 that interacts with BIR3 also mediates its homodimerization. Monomeric caspase-9 is catalytically inactive due to the absence of a supporting sequence element that could be provided by homodimerization. The authors concluded that XIAP sequesters caspase-9 in a monomeric state, which serves to prevent catalytic activity. </p><p><strong><em>Solution Structure</em></strong></p><p>
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To understand the structural basis of molecular recognition between SMAC and the IAPs, Liu et al. (2000) determined the solution structure of the BIR3 domain of XIAP complexed with a functionally active 9-residue peptide derived from the N terminus of SMAC. Wu et al. (2000) performed the same experiment. They found that the N-terminal 4 residues (ala-val-pro-ile) in SMAC/DIABLO recognize a surface groove on BIR3, with the first residue ala binding a hydrophobic pocket and making 5 hydrogen bonds to neighboring residues on BIR3. These observations provided a structural explanation for the roles of the SMAC N terminus as well as for the conserved N-terminal sequences in the Drosophila proteins Hid/Grim/Reaper. In conjunction with other observations, Wu et al. (2000) concluded that their results reveal how SMAC may relieve IAP inhibition of caspase-9 activity. In addition to explaining a number of biologic observations, both Liu et al. (2000) and Wu et al. (2000) suggested that their structural analyses identified potential targets for drug screening that may be used for the treatment of cancers that overexpress IAPs. </p>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>Rigaud et al. (2006) determined that the XIAP gene comprises 6 exons. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Rajcan-Separovic et al. (1996) used fluorescence in situ hybridization (FISH) to map the XIAP gene to chromosome Xq25. By FISH, Farahani et al. (1997) mapped the mouse miap3 gene to the X chromosome, region A3-A5. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p>In affected males from 3 families with X-linked lymphoproliferative syndrome-2 (XLP2; 300635), Rigaud et al. (2006) identified hemizygous frameshift, nonsense, and deletion mutations in the XIAP gene (300079.0001-300079.0003). Despite similarities in clinical features, patients with XIAP deficiency showed different cellular manifestations than did patients with SAP deficiency (XLP1; 308240). Rigaud et al. (2006) showed that apoptosis of lymphocytes from XIAP-deficient patients is enhanced in response to various stimuli, including the T-cell antigen receptor (TCR)-CD3 complex (see 186790), the death receptor CD95 (134637), and the TNF-associated apoptosis-inducing ligand receptor (TRAILR; see 603613). Rigaud et al. (2006) also found that XIAP-deficient patients, like SAP-deficient patients, have low numbers of natural killer T lymphocytes (NKT cells), indicating that XIAP is required for the survival and/or differentiation of NKT cells. The observation that XIAP deficiency and SAP deficiency are both associated with a defect in NKT cells strengthened the hypothesis that NKT cells have a key role in the immune response to Epstein-Barr virus (EBV). Furthermore, by identifying an XLP immunodeficiency that is caused by mutations in XIAP, Rigaud et al. (2006) showed that XIAP is a potent regulator of lymphocyte homeostasis in vivo. </p><p>Worthey et al. (2011) identified a missense mutation of a highly conserved cysteine in the XIAP gene in a child with XLP2 manifesting as intractable inflammatory bowel disease (300079.0004). </p><p>In 9 Japanese male patients from 6 unrelated Japanese families with XLP2, Yang et al. (2012) identified 6 different truncating mutations in the XIAP gene (see, e.g., 300079.0005-300079.0007). The mutations were found by direct screening of the XIAP gene after exclusion of mutations in the SH2D1A gene (300490). The mothers of patients from families 1 through 5 were heterozygous carriers of the mutations, whereas the mother of 2 sibs (family 6) did not carry the mutation in peripheral blood, suggesting germline mosaicism. Flow cytometric analysis of patient lymphocytes showed decreased expression in 7 of 8 patients; low-normal expression was found in a patient (patient 4) with an in-frame deletion mutation (E349del; 300079.0005) who had a milder phenotype with only hypogammaglobulinemia and recurrent infections. The expression pattern of XIAP in carrier mother cells was variably reduced or showed a bimodal pattern. Western blot analysis, performed on 3 patients, showed decreased XIAP levels. </p><p>In 6 affected males from a large Caucasian family with XLP2, Dziadzio et al. (2015) identified a truncating mutation in the XIAP gene (300079.0008). There were 7 female carriers, 6 of whom were symptomatic to varying degrees. Flow cytometric analysis of peripheral cells from 1 of the affected males showed absence of the XIAP protein and a severely abrogated response of monocytes to NOD2 (605956), with decreased TNF-alpha (191160) production. Flow cytometric analysis of lymphocyte subsets and monocytes from 3 female carriers showed revealed preferential expression of XIAP wildtype protein and normal NOD2 function. However, the most severely affected female carrier (patient IV.9) with IBD and erythema nodosum (EN) had random X-inactivation, resulting in expression of the mutated XIAP protein in her monocytes and impaired NOD2 responses in vitro. These findings indicated that the pattern of X-inactivation can influence the phenotype in female carriers. The findings also indicated that impaired NOD2 signaling is a driving pathophysiologic mechanism of the disorder. In addition, the truncated mutation also resulted in increased activation-induced cell death (AICD) of patient-derived T-cell blasts in vitro, suggesting that the mutation also affected the antiapoptotic properties of XIAP. </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>Harlin et al. (2001) generated mice deficient in Xiap through homologous gene targeting. The Xiap -/- mice were viable, histopathologically normal, and lacked defects in caspase-dependent or -independent apoptosis. However, the levels of Ciap1 and Ciap2 were increased, suggesting the existence of a compensatory mechanism in the absence of XIAP expression that may be provided by these molecules. </p><p>In a review, Latour and Aguilar (2015) noted that studies have shown that certain strains of Xiap-deficient mice have compromised immunity leading to decreased survival when infected with certain pathogens, including intracellular bacteria and viruses. These infections are associated with splenomegaly and compromised innate immunity with altered cytokine production. </p><p>In bone marrow-derived macrophages (BMDMs) from Xiap-deficient mice, Chiang et al. (2022) demonstrated that Il1-beta (147720) was produced in response to stimulation with Tnf-alpha (191160) or Tlr (see 601194) agonists without the requirement of a second activation signal. This second activation signal was required by wildtype BMDMs. Furthermore, in BMDMs derived from mice that were deficient in both Xiap and Nrpl3 (600928), IL1-beta production was reduced compared to BMDMs from Xiap-deficient mice. Chiang et al. (2022) concluded that the NLRP3 inflammasome complex plays a role in the hyperinflammation in X-linked lymphoproliferative syndrome. When the Xiap-deficient BMDMs were treated with MCC950 (an NLRP3 inhibitor), chloroquine (an inhibitor of lysosome acidification) or quercetin (an antioxidant), Il1-beta overproduction was abrogated. Chiang et al. (2022) showed that treated Xiap-deficient mice with quercetin had reduced cytokine production after LPS exposure compared to untreated Xiap-deficient mice. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>8 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 2</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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XIAP, 1-BP DEL, 291C
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<br />
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SNP: rs1556404534,
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ClinVar: RCV000012411
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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 affected males from a family (family 1) with X-linked lymphoproliferative syndrome (XLP2; 300635), Rigaud et al. (2006) detected hemizygosity for deletion of the cytidine at nucleotide position 291 of the XIAP gene (c.291delC), resulting in a frameshift leading to a stop codon at position 387 (G99K/X129). </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 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 2</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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XIAP, GLU118TER
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<br />
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SNP: rs104894764,
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ClinVar: RCV000012412
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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 affected males from a family (family 3) with X-linked lymphoproliferative syndrome (XLP2; 300635), Rigaud et al. (2006) identified a hemizygous c.352G-T transversion in the XIAP gene, resulting in a glu118-to-ter (E118X) substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 2</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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XIAP, 2606-BP DEL
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<br />
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ClinVar: RCV000012413
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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 affected males from a family (family 2) with X-linked lymphoproliferative syndrome (XLP2; 300635), Rigaud et al. (2006) detected a hemizygous deletion of 2,606 nucleotides encompassing exon 2 of the XIAP gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 2</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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XIAP, CYS203TYR
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<br />
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SNP: rs387907301,
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gnomAD: rs387907301,
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ClinVar: RCV000030806
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a boy with X-linked lymphoproliferative syndrome (XLP2; 300635) manifesting as intractable inflammatory bowel disease, Worthey et al. (2011) undertook whole-exome sequencing and identified a hemizygous G-to-A substitution at a highly conserved position in the XIAP gene, resulting in a hemizygous cys-to-tyr amino acid substitution at codon 203 (C203Y). This mutation was not found in more than 2,000 human control sequences or in orthologous genes from other species down to Drosophila. Confirmation of the variant in the child was carried out by Sanger sequencing, and studies on the mother confirmed the mutation and showed maternal skewed X-chromosome inactivation in natural killer, B, and T helper cell types. Functional assays demonstrated an increased susceptibility to activation-induced cell death and defective responsiveness to NOD2 (605956) ligands, consistent with loss of normal XIAP function in apoptosis and NOD2 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>
|
|
<span class="mim-font">
|
|
<strong>.0005 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 2</strong>
|
|
</span>
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</h4>
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</div>
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<div>
|
|
<span class="mim-text-font">
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|
XIAP, 3-BP DEL, 1045GAG ({dbSNP rs199683465})
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|
<br />
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|
|
SNP: rs199683465,
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|
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|
|
|
gnomAD: rs199683465,
|
|
|
|
|
|
ClinVar: RCV000490405, RCV003325468, RCV003967566
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 15-year-old Japanese boy (patient 4) with X-linked lymphoproliferative syndrome (XLP2; 300635) manifesting only as hypogammaglobulinemia with recurrent infections, Yang et al. (2012) identified a hemizygous in-frame 3-bp deletion (c.1045_1047delGAG) in exon 3 of the XIAP gene, resulting in a deletion of residue glu349 (E349del). Flow cytometric analysis of patient lymphocytes detected normal levels of XIAP. </p><p>Nishida et al. (2015) identified 3 additional Japanese boys (patients 4, 9, and 10) with XLP2 due to a hemizygous E349del variant. The disorder manifested as hypogammaglobulinemia only, although 1 of the patients developed aplastic anemia requiring hematopoietic stem cell transplantation. The patients had normal XIAP protein expression, but decreased numbers of CD19+ switched memory B cells. Patient cells did not showed increased activation-induced cell death (AICD) of T lymphocytes compared to controls. Microarray analysis indicated that the gene expression patterns were different in patients with the E349del mutation compared to patients with other mutations in the XIAP gene. Patients with E349del had 10-fold lower expression of a number of genes, including those involved in B cell development and Ig levels. Nishida et al. (2015) stated that the variant occurred in exon 4 of the XIAP gene and that it was a polymorphism in the Japanese population. Among 170 healthy Japanese individuals, 2 were heterozygous and 4 homozygous for the variant. Nishida et al. (2015) concluded that although the E349del variant is a SNP, it could be associated with hypo/dysgammaglobulinemia. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
XIAP, 2-BP DEL, 1021AA
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs1556406033,
|
|
|
|
|
|
|
|
ClinVar: RCV000515791
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Japanese brothers (patient 6.1 and 6.2) with X-linked lymphoproliferative syndrome (XLP2; 300635), Yang et al. (2012) identified a hemizygous 2-bp deletion (c.1021_1022delAA) in exon 3, resulting in a frameshift and premature termination (Asn341TyrfsTer7). The mutation was not detected in the mother's lymphocytes, suggesting germline mosaicism. Flow cytometric and Western blot analysis of patient lymphocytes showed decreased levels of XIAP, consistent with a loss of function. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
XIAP, 1-BP DEL, 650G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1556404673,
|
|
|
|
|
|
|
|
ClinVar: RCV000515801
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Japanese brothers (patients 3.1 and 3.2) with X-linked lymphoproliferative syndrome (XLP2; 300635), Yang et al. (2012) identified a hemizygous 1-bp deletion (c.650delG) in exon 1 of the XIAP gene, resulting in a frameshift and premature termination (Trp217CysfsTer27). Interestingly, 1 patient had a severe disorder with onset at age 2 months and recurrent EBV-associated HLH, whereas the other was asymptomatic at age 17 years. Flow cytometric and Western blot analysis of patient lymphocytes showed decreased levels of XIAP. </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>.0008 LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
XIAP, 1-BP DUP, 672T
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|
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|
|
<br />
|
|
|
|
SNP: rs1556404697,
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|
|
|
|
|
ClinVar: RCV000515784
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 6 affected males from a large Caucasian family with X-linked lymphoproliferative syndrome (XLP2; 300635), Dziadzio et al. (2015) identified a 1-bp duplication (c.672dupT) in exon 2 of the XIAP gene, resulting in a frameshift and premature termination (Pro225SerfsTer2) in the BIR2 domain. Four of 5 affected males had severe inflammatory bowel disease (IBD), and 6 of 7 carrier females had chronic erythema nodosum (EN) and variable bowel symptoms. One female carrier was asymptomatic. Flow cytometric analysis of peripheral blood cells from 1 of the affected males showed absence of the XIAP protein and a severely abrogated response of monocytes to NOD2. Flow cytometric analysis of lymphocyte subsets and monocytes from 3 female carriers showed preferential expression of XIAP wildtype protein and normal NOD2 function. However, the most severely affected female carrier (patient IV.9) with IBD and EN had expression of mutated XIAP protein in her monocytes, leading to impaired NOD2 responses in vitro. These observations indicated that impaired NOD2 signaling is a driving pathophysiologic mechanism of the disorder. In addition, the truncated mutation also resulted in increased activation-induced cell death (AICD) of patient-derived T-cell blasts in vitro, suggesting that the mutation also affects the antiapoptotic properties of XIAP. </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>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
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</h4>
|
|
<div>
|
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<p />
|
|
</div>
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<div>
|
|
<ol>
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<li>
|
|
<p class="mim-text-font">
|
|
Chai, J., Shiozaki, E., Srinivasula, S. M., Wu, Q., Datta, P., Alnemri, E. S., Shi, Y.
|
|
<strong>Structural basis of caspase-7 inhibition by XIAP.</strong>
|
|
Cell 104: 769-780, 2001. Note: Erratum: Cell 107: 409 only, 2001.
|
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|
|
[PubMed: 11257230]
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[Full Text: https://doi.org/10.1016/s0092-8674(01)00272-0]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Chiang, S. C. C., Owsley, E., Panchal, N., Chaturvedi, V., Terrell, C. E., Jordan, M. B., Mehta, P. A., Davies, S. M., Akeno, N., Booth, C., Marsh, R. A.
|
|
<strong>Quercetin ameliorates XIAP deficiency-associated hyperinflammation.</strong>
|
|
Blood 140: 706-715, 2022.
|
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|
|
[PubMed: 35687753]
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|
[Full Text: https://doi.org/10.1182/blood.2021014335]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Cummins, J. M., Kohli, M., Rago, C., Kinzler, K. W., Vogelstein, B., Bunz, F.
|
|
<strong>X-linked inhibitor of apoptosis protein (XIAP) is a nonredundant modulator of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human cancer cells.</strong>
|
|
Cancer Res. 64: 3006-3008, 2004.
|
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|
|
[PubMed: 15126334]
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|
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[Full Text: https://doi.org/10.1158/0008-5472.can-04-0046]
|
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Deveraux, Q. L., Takahashi, R., Salvesen, G. S., Reed, J. C.
|
|
<strong>X-linked IAP is a direct inhibitor of cell-death proteases.</strong>
|
|
Nature 388: 300-304, 1997.
|
|
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|
|
[PubMed: 9230442]
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|
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[Full Text: https://doi.org/10.1038/40901]
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</p>
|
|
</li>
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<li>
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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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Hilary J. Vernon - updated : 03/30/2023<br>Bao Lige - updated : 01/12/2022<br>Cassandra L. Kniffin - updated : 11/28/2017<br>Ada Hamosh - updated : 9/28/2012<br>Ada Hamosh - updated : 9/15/2009<br>Patricia A. Hartz - updated : 8/13/2009<br>Patricia A. Hartz - updated : 8/6/2007<br>Ada Hamosh - updated : 1/10/2007<br>Patricia A. Hartz - updated : 4/10/2006<br>Patricia A. Hartz - updated : 8/17/2004<br>Stylianos E. Antonarakis - updated : 4/21/2003<br>Patricia A. Hartz - updated : 11/8/2002<br>Paul J. Converse - updated : 4/23/2002<br>Paul J. Converse - updated : 11/14/2001<br>Stylianos E. Antonarakis - updated : 4/16/2001<br>Ada Hamosh - updated : 5/4/2000<br>Rebekah S. Rasooly - updated : 2/22/1999<br>Victor A. McKusick - updated : 9/9/1997<br>Jennifer P. Macke - updated : 7/29/1997
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Jennifer P. Macke : 3/24/1997
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carol : 03/31/2023<br>mgross : 01/18/2022<br>mgross : 01/12/2022<br>alopez : 12/05/2017<br>ckniffin : 11/28/2017<br>carol : 09/14/2016<br>terry : 04/04/2013<br>alopez : 10/2/2012<br>terry : 9/28/2012<br>wwang : 1/5/2011<br>alopez : 9/15/2009<br>terry : 9/15/2009<br>mgross : 8/13/2009<br>terry : 8/13/2009<br>mgross : 8/9/2007<br>terry : 8/6/2007<br>alopez : 1/16/2007<br>terry : 1/10/2007<br>terry : 1/10/2007<br>mgross : 4/12/2006<br>terry : 4/10/2006<br>mgross : 8/26/2004<br>terry : 8/17/2004<br>carol : 11/12/2003<br>carol : 7/24/2003<br>mgross : 4/21/2003<br>mgross : 11/8/2002<br>mgross : 4/23/2002<br>mgross : 2/18/2002<br>alopez : 11/14/2001<br>alopez : 11/14/2001<br>mgross : 4/16/2001<br>mgross : 4/16/2001<br>alopez : 2/28/2001<br>carol : 12/23/2000<br>mgross : 9/15/2000<br>alopez : 5/4/2000<br>alopez : 2/22/1999<br>alopez : 2/22/1999<br>alopez : 12/22/1998<br>carol : 9/22/1998<br>alopez : 11/24/1997<br>jenny : 9/18/1997<br>terry : 9/9/1997<br>alopez : 9/8/1997<br>alopez : 9/5/1997<br>terry : 7/29/1997<br>alopez : 7/1/1997<br>alopez : 4/2/1997<br>alopez : 3/31/1997<br>alopez : 3/25/1997<br>alopez : 3/24/1997
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