3625 lines
332 KiB
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3625 lines
332 KiB
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Entry
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- *134638 - FAS LIGAND; FASLG
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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">*134638</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/134638">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000117560;t=ENST00000367721" 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=356" 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=134638" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000117560;t=ENST00000367721" 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_000639,NM_001302746" 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_000639" 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=134638" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
|
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=00610&isoform_id=00610_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/FASLG" 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/595431,624628,887456,1345957,1369902,2665473,3201668,3492847,4557329,12597289,17028381,28569614,61658441,117606530,119611341,119611342,189054595,226888194,311461934,333107392,720642745,768031939,972853667" 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/P48023" 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=356" 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=ENSG00000117560;t=ENST00000367721" 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=FASLG" 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=FASLG" 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+356" 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/FASLG" 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:356" 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/356" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr1&hgg_gene=ENST00000367721.3&hgg_start=172659103&hgg_end=172666876&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:11936" 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://search.clinicalgenome.org/kb/genes/HGNC:11936" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=134638[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=134638[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/ENSG00000117560" 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.gwascentral.org/search?q=FASLG" 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=FASLG" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://structure.bmc.lu.se/idbase/FASLGbase/" title="FASLGbase: Mutation registry for Autoimmune lymphoproliferative syndrome, type 1B (ALPS1B) (previously known as TNFSF6base)" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">FASLGbase: Mutation regist…</a></div><div style="margin-left: 0.5em;"><a href="https://research.cchmc.org/LOVD2/home.php?select_db=FASLG" title="CCHMC - Human Genetics Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">CCHMC - Human Genetics Mut…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=FASLG&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/PA56" 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:11936" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:99255" 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/FASLG#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:99255" 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/356/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://omia.org/OMIA002064/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=356" 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-070410-16" 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:356" 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=FASLG&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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134638
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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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FAS LIGAND; FASLG
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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">
|
|
FASL<br />
|
|
TUMOR NECROSIS FACTOR LIGAND SUPERFAMILY, MEMBER 6; TNFSF6<br />
|
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APOPTOSIS ANTIGEN LIGAND 1; APT1LG1<br />
|
|
APOPTOSIS ANTIGEN LIGAND<br />
|
|
CD95 LIGAND; CD95L<br />
|
|
CD178 ANTIGEN; CD178
|
|
</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=FASLG" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FASLG</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/1/1427?start=-3&limit=10&highlight=1427">1q24.3</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:172659103-172666876&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">1:172,659,103-172,666,876</a> </span>
|
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</em>
|
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</strong>
|
|
<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>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=211980,601859" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/1427?start=-3&limit=10&highlight=1427">
|
|
1q24.3
|
|
</a>
|
|
</span>
|
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</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Lung cancer, susceptibility to}
|
|
|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/211980"> 211980 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Somatic mutation">SMu</abbr>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<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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|
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Autoimmune lymphoproliferative syndrome, type IB
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/601859"> 601859 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
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<p>Life requires death. Elimination of unwanted cells is vital for embryogenesis, metamorphosis and tissue turnover, as well as for the development and function of the immune system. Mammalian development is tightly regulated not only by the proliferation and differentiation of cells but also by cell death. The cell death that occurs during development or tissue turnover is called programmed cell death, most of which proceeds via apoptosis. Apoptosis is morphologically distinguished from necrosis, which occurs during the accidental cell death caused by physical or chemical agents. During apoptosis, the cytoplasm of the affected cells condenses, and the nucleus also condenses and becomes fragmented. At the final stage of apoptosis, the cells themselves are fragmented (apoptotic bodies) and are phagocytosed by neighboring macrophages and granulocytes. Apoptosis occurs not only during programmed cell death, but also during the death process induced by some cytotoxic T cells. <a href="#20" class="mim-tip-reference" title="Suda, T., Takahashi, T., Golstein, P., Nagata, S. <strong>Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family.</strong> Cell 75: 1169-1178, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7505205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7505205</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90326-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7505205">Suda et al. (1993)</a> identified the ligand that triggers cell death by binding to the cell surface receptor variously known as FAS or APT1 (TNFRSF6; <a href="/entry/134637">134637</a>). This cell surface receptor was discovered in 1989 with the isolation of 2 monoclonal antibodies (anti-Fas and anti-Apo-1) that had the startling property of killing a human cell line used as the immunogen. Cell death occurred by apoptosis. Cloning of the genes revealed that the antigens recognized by the 2 monoclonal antibodies were one and the same. It is a transmembrane protein related to a family of receptors that includes the 2 tumor necrosis factor (TNF) receptors (<a href="/entry/191190">191190</a>, <a href="/entry/191191">191191</a>). In mice, mutations at the lpr (lymphoproliferation) locus have a defect in the FAS antigen. The inability of homozygous mutant mice to mediate FAS-induced apoptosis provokes a complex immunologic disorder featuring defects in both the B and T lymphoid compartments. A very similar phenotype of mice homozygous for the gld (generalized lymphoproliferative disease) mutation suggested that the gld gene encodes the ligand for FAS. <a href="#20" class="mim-tip-reference" title="Suda, T., Takahashi, T., Golstein, P., Nagata, S. <strong>Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family.</strong> Cell 75: 1169-1178, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7505205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7505205</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90326-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7505205">Suda et al. (1993)</a> isolated the ligand from a cytotoxic T hybridoma by a sensitive expression cloning strategy. The amino acid sequence indicated that FAS ligand is a type II transmembrane protein that belongs to the tumor necrosis factor family. Northern hybridization revealed that the ligand is expressed in activated splenocytes and thymocytes, consistent with its involvement in T cell-mediated cytotoxicity, and in several nonlymphoid tissues, such as testis. The FAS antigen is expressed not only in the cells of the immune system but also in the liver, lung, ovary, and heart, where its function was unclear. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7505205" 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="Takahashi, T., Tanaka, M., Inazawa, J., Abe, T., Suda, T., Nagata, S. <strong>Human Fas ligand: gene structure, chromosomal location and species specificity.</strong> Int. Immun. 6: 1567-1574, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7826947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7826947</a>] [<a href="https://doi.org/10.1093/intimm/6.10.1567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7826947">Takahashi et al. (1994)</a> isolated the chromosomal gene for human FasL. The human FASL cDNA predicted a type II membrane protein consisting of 281 amino acids and a calculated M(r) of 31,759 that showed 76.9% amino acid sequence identity with the mouse protein. When expressed in COS cells, both human and mouse recombinant FasL induced apoptosis, indicating crossreactivity. A sequence of approximately 300 bp upstream of the ATG initiation codon was found to be highly conserved between mouse and human. Several transcription cis-regulatory elements such as SP1 (<a href="/entry/189906">189906</a>), NF-kappa-B (see <a href="/entry/164011">164011</a>), and IRF1 (<a href="/entry/147575">147575</a>) were recognized in this region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7826947" 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="mim-changed mim-change"><p><a href="#23" class="mim-tip-reference" title="Takahashi, T., Tanaka, M., Inazawa, J., Abe, T., Suda, T., Nagata, S. <strong>Human Fas ligand: gene structure, chromosomal location and species specificity.</strong> Int. Immun. 6: 1567-1574, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7826947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7826947</a>] [<a href="https://doi.org/10.1093/intimm/6.10.1567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7826947">Takahashi et al. (1994)</a> determined that the human FASL gene contains 4 exons and spans approximately 8 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7826947" 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></div>
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<div class="mim-changed mim-change"><p><a href="#23" class="mim-tip-reference" title="Takahashi, T., Tanaka, M., Inazawa, J., Abe, T., Suda, T., Nagata, S. <strong>Human Fas ligand: gene structure, chromosomal location and species specificity.</strong> Int. Immun. 6: 1567-1574, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7826947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7826947</a>] [<a href="https://doi.org/10.1093/intimm/6.10.1567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7826947">Takahashi et al. (1994)</a> mapped the human FASL gene to chromosome 1q23 by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7826947" 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></div>
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<div class="mim-changed mim-change"><p>By interspecific backcross analysis, <a href="#22" class="mim-tip-reference" title="Takahashi, T., Tanaka, M., Brannan, C. I., Jenkins, N. A., Copeland, N. G., Suda, T., Nagata, S. <strong>Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand.</strong> Cell 76: 969-976, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7511063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7511063</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90375-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7511063">Takahashi et al. (1994)</a> localized the murine Fasl gene to the gld region of mouse chromosome 1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7511063" 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></div>
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<p><a href="#22" class="mim-tip-reference" title="Takahashi, T., Tanaka, M., Brannan, C. I., Jenkins, N. A., Copeland, N. G., Suda, T., Nagata, S. <strong>Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand.</strong> Cell 76: 969-976, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7511063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7511063</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90375-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7511063">Takahashi et al. (1994)</a> isolated the murine Fasl gene and showed that activated splenocytes from 'generalized lymphoproliferative disease' (gld) mice express Fasl mRNA. However, the Fas ligand protein in gld mice carried a point mutation in the C-terminal region, which is highly conserved among members of the TNF family. Recombinant gld Fas ligand expressed in COS cells could not induce apoptosis in cells expressing Fas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7511063" 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>Testis is a remarkably immune-privileged site, long known for its ability to support allogeneic and xenogeneic tissue transplants. <a href="#2" class="mim-tip-reference" title="Bellgrau, D., Gold, D., Selawry, H., Moore, J., Franzusoff, A., Duke, R. C. <strong>A role for CD95 ligand in preventing graft rejection.</strong> Nature 377: 630-632, 1995. Note: Erratum: Nature 394: 133 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7566174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7566174</a>] [<a href="https://doi.org/10.1038/377630a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7566174">Bellgrau et al. (1995)</a> reported results suggesting that expression of FasL by Sertoli cells accounts for the immune-privileged nature of testis. Testis grafts derived from mice that can express functional FasL survived indefinitely when transplanted under the kidney capsule of allogeneic mice, whereas testis graft derived from mutant gld mice, which express nonfunctional ligand, were rejected. The authors speculated that FasL expression in the testis probably acts by inducing apoptotic cell death of Fas-expressing, recipient T cells activated in response to graft antigens. <a href="#4" class="mim-tip-reference" title="D'Alessio, A., Riccioli, A., Lauretti, P., Padula, F., Muciaccia, B., De Cesaris, P., Filippini, A., Nagata, S., Ziparo, E. <strong>Testicular FasL is expressed by sperm cells.</strong> Proc. Nat. Acad. Sci. 98: 3316-3321, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11248076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11248076</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11248076[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.051566098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11248076">D'Alessio et al. (2001)</a> demonstrated that the attribution of testicular expression of FasL to Sertoli cells is erroneous and that FasL transcription instead occurs in meiotic and postmeiotic germ cells, whereas the protein is only displayed on mature spermatozoa. These findings point to a significant role of the Fas system in the biology of mammalian reproduction. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11248076+7566174" 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="Hahne, M., Rimoldi, D., Schroter, M., Romero, P., Schreier, M., French, L. E., Schneider, P., Bornand, T., Fontana, A., Lienard, D., Cerottini, J. C., Tschopp, J. <strong>Melanoma cell expression of Fas (Apo-1/CD95) ligand: implications for tumor immune escape.</strong> Science 274: 1363-1366, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8910274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8910274</a>] [<a href="https://doi.org/10.1126/science.274.5291.1363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8910274">Hahne et al. (1996)</a> stated that, despite the existence of melanoma-specific cytolytic T cells in tumor-infiltrating lymphocytes and in peripheral blood from melanoma patients, and the definition of 12 CTL-defined melanoma peptide antigens, melanoma cells are able to avoid immune detection in most instances. The investigators proposed that FASL-expressing melanoma cells may kill FAS (<a href="/entry/134637">134637</a>)-sensitive activating T lymphocytes. They analyzed FASL expression in melanoma cells and demonstrated substantial quantities of FASL in lysates of a series of human melanoma cells. Two molecular species were identified: a 40-kD membrane-bound FASL and a 27-kD extracellular FASL. <a href="#8" class="mim-tip-reference" title="Hahne, M., Rimoldi, D., Schroter, M., Romero, P., Schreier, M., French, L. E., Schneider, P., Bornand, T., Fontana, A., Lienard, D., Cerottini, J. C., Tschopp, J. <strong>Melanoma cell expression of Fas (Apo-1/CD95) ligand: implications for tumor immune escape.</strong> Science 274: 1363-1366, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8910274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8910274</a>] [<a href="https://doi.org/10.1126/science.274.5291.1363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8910274">Hahne et al. (1996)</a> also demonstrated that the majority of cells infiltrating the tumors were FAS-positive. No FASL was found in normal melanocytes of the skin, suggesting that FASL upregulation occurs during tumorigenesis. <a href="#8" class="mim-tip-reference" title="Hahne, M., Rimoldi, D., Schroter, M., Romero, P., Schreier, M., French, L. E., Schneider, P., Bornand, T., Fontana, A., Lienard, D., Cerottini, J. C., Tschopp, J. <strong>Melanoma cell expression of Fas (Apo-1/CD95) ligand: implications for tumor immune escape.</strong> Science 274: 1363-1366, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8910274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8910274</a>] [<a href="https://doi.org/10.1126/science.274.5291.1363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8910274">Hahne et al. (1996)</a> proposed that FASL-expressing melanoma cells might induce apoptosis of FAS-sensitive tumor infiltrating cells. They reported that injection of FasL+ mouse melanoma cells in mice led to rapid tumor formation. When FasL+ mouse melanoma cells were injected into FAS-deficient mutant mice, tumorigenesis was delayed. These findings led <a href="#8" class="mim-tip-reference" title="Hahne, M., Rimoldi, D., Schroter, M., Romero, P., Schreier, M., French, L. E., Schneider, P., Bornand, T., Fontana, A., Lienard, D., Cerottini, J. C., Tschopp, J. <strong>Melanoma cell expression of Fas (Apo-1/CD95) ligand: implications for tumor immune escape.</strong> Science 274: 1363-1366, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8910274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8910274</a>] [<a href="https://doi.org/10.1126/science.274.5291.1363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8910274">Hahne et al. (1996)</a> to conclude that FASL may contribute to the immune privilege of tumors. They proposed further that pharmacologic products that render infiltrating T cells insensitive to FASL-induced killing may break the immunologic unresponsiveness to melanoma and provide a complementary approach in the therapy of malignant melanoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8910274" 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 the United States more than 43,000 corneal transplants are performed each year, making it the most common form of solid tissue transplantation, and second only to bone marrow transplants in overall numbers performed. Corneal transplantation is also one of the most successful types of transplantation with failure rates at only 10 to 15% after 1 year and approximately 30% after 5 years. <a href="#19" class="mim-tip-reference" title="Stuart, P. M., Griffith, T. S., Usui, N., Pepose, J., Yu, X., Ferguson, T. A. <strong>CD95 ligand (FasL)-induced apoptosis is necessary for corneal allograft survival.</strong> J. Clin. Invest. 99: 396-402, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9022072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9022072</a>] [<a href="https://doi.org/10.1172/JCI119173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9022072">Stuart et al. (1997)</a> demonstrated that the very high percentage of successful corneal transplants, without tissue matching or immunosuppressant therapy, is related to the expression of abundant functional FASL in the cornea, capable of killing FASL(+) lymphoid cells. Using a mouse model for corneal allograft transplantation, FasL(+) orthografts were accepted at a rate of 45%, whereas FasL(-) or normal grafts transplanted to Fas(-) mice were rejected 100% of the time. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9022072" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Viard, I., Wehrli, P., Bullani, R., Schneider, P., Holler, N., Salomon, D., Hunziker, T., Saurat, J.-H., Tschopp, J., French, L. E. <strong>Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin.</strong> Science 282: 490-493, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774279</a>] [<a href="https://doi.org/10.1126/science.282.5388.490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774279">Viard et al. (1998)</a> detected high levels of soluble FASL in the sera of patients with toxic epidermal necrolysis (TEN; <a href="/entry/608579">608579</a>). Keratinocytes of TEN patients produced FASL, which induced keratinic apoptosis. Incubating keratinocytes with intravenous immunoglobulin (IVIG) completely inhibited FAS-mediated keratinocyte apoptosis. A naturally occurring anti-FAS immunoglobulin present in IVIG blocks the FAS receptor and mediates this response. Ten patients with TEN were treated with IVIG. Progression of skin disease was rapidly reversed in all cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9774279" 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>DNA-damaged cells can either repair the DNA or be eliminated through a homeostatic control mechanism mediated by p53 (<a href="/entry/191170">191170</a>) termed 'cellular proofreading.' Elimination of DNA-damaged cells after UV radiation through sunburn cell (or apoptotic keratinocyte) formation is thought to be pivotal for the removal of precancerous skin cells. <a href="#10" class="mim-tip-reference" title="Hill, L. L., Ouhtit, A., Loughlin, S. M., Kripke, M. L., Ananthaswamy, H. N., Owen-Schaub, L. B. <strong>Fas ligand: a sensor for DNA damage critical in skin cancer etiology.</strong> Science 285: 898-900, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10436160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10436160</a>] [<a href="https://doi.org/10.1126/science.285.5429.898" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10436160">Hill et al. (1999)</a> demonstrated that sunburn cell formation is dependent upon FasL. Chronic exposure to UV radiation caused 14 of 20, or 70%, of FasL-deficient mice and 1 of 20, or 5%, of wildtype mice to accumulate p53 mutations in the epidermis. <a href="#10" class="mim-tip-reference" title="Hill, L. L., Ouhtit, A., Loughlin, S. M., Kripke, M. L., Ananthaswamy, H. N., Owen-Schaub, L. B. <strong>Fas ligand: a sensor for DNA damage critical in skin cancer etiology.</strong> Science 285: 898-900, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10436160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10436160</a>] [<a href="https://doi.org/10.1126/science.285.5429.898" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10436160">Hill et al. (1999)</a> concluded that FASL-mediated apoptosis is important for skin homeostasis, suggesting that the dysregulation of FAS-FASL interactions may be central to the development of skin cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10436160" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Pestano, G. A., Zhou, Y., Trimble, L. A., Daley, J., Weber, G. F., Cantor, H. <strong>Inactivation of misselected CD8 T cells by CD8 gene methylation and cell death.</strong> Science 284: 1187-1191, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10325233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10325233</a>] [<a href="https://doi.org/10.1126/science.284.5417.1187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10325233">Pestano et al. (1999)</a> identified a differentiative pathway taken by CD8 cells bearing receptors that cannot engage class I MHC (see <a href="/entry/142800">142800</a>) self-peptide molecules because of incorrect thymic selection, defects in peripheral MHC class I expression, or antigen presentation. In any of these cases, failed CD8 T-cell receptor coengagement results in downregulation of genes that account for specialized cytolytic T-lymphocyte function and resistance to cell death (CD8-alpha/beta, see <a href="/entry/186730">186730</a>; granzyme B, <a href="/entry/123910">123910</a>; and LKLF, <a href="/entry/602016">602016</a>), and upregulation of Fas and FasL death genes. Thus, MHC engagement is required to inhibit expression and delivery of a death program rather than to supply a putative trophic factor for T cell survival. <a href="#16" class="mim-tip-reference" title="Pestano, G. A., Zhou, Y., Trimble, L. A., Daley, J., Weber, G. F., Cantor, H. <strong>Inactivation of misselected CD8 T cells by CD8 gene methylation and cell death.</strong> Science 284: 1187-1191, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10325233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10325233</a>] [<a href="https://doi.org/10.1126/science.284.5417.1187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10325233">Pestano et al. (1999)</a> hypothesized that defects in delivery of the death signal to these cells underlie the explosive growth and accumulation of double-negative T cells in animals bearing Fas and FasL mutations, in patients that carry inherited mutations of these genes, and in about 25% of systemic lupus erythematosus patients that display the cellular signature of defects in this mechanism of quality control of CD8 cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10325233" 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="#7" class="mim-tip-reference" title="Grassme, H., Kirschnek, S., Riethmueller, J., Riehle, A., von Kurthy, G., Lang, F., Weller, M., Gulbins, E. <strong>CD95/CD95 ligand interactions on epithelial cells in host defense to Pseudomonas aeruginosa.</strong> Science 290: 527-530, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11039936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11039936</a>] [<a href="https://doi.org/10.1126/science.290.5491.527" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11039936">Grassme et al. (2000)</a> showed that Pseudomonas aeruginosa infection induces apoptosis of lung epithelial cells by activation of the endogenous CD95/CD95L system. Deficiency of CD95 or CD95L on epithelial cells prevented apoptosis of lung epithelial cells in vivo as well as in vitro. The importance of CD95/CD95L-mediated lung epithelial cell apoptosis was demonstrated by the rapid development of sepsis in mice deficient in either CD95 or CD95L, but not in normal mice, after P. aeruginosa infection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11039936" 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>Cytomegalovirus (CMV) is a persistent viral pathogen that resides in monocyte/macrophages and dendritic cells (DCs), critical antigen-presenting cells in the immune system. In fetal and compromised immune systems, CMV can be fatal. <a href="#17" class="mim-tip-reference" title="Raftery, M. J., Schwab, M., Eibert, S. M., Samstag, Y., Walczak, H., Schonrich, G. <strong>Targeting the function of mature dendritic cells by human cytomegalovirus: a multilayered viral defense strategy.</strong> Immunity 15: 997-1009, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11754820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11754820</a>] [<a href="https://doi.org/10.1016/s1074-7613(01)00239-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11754820">Raftery et al. (2001)</a> found that recent CMV isolates, but not fibroblast-adapted CMV strains, could infect mature DCs with no change in some cell surface markers. On the other hand, flow cytometric analysis indicated a slight upregulation of the costimulatory molecules CD40 (<a href="/entry/109535">109535</a>), CD80 (<a href="/entry/112203">112203</a>), and CD86 (<a href="/entry/601020">601020</a>), as well as a downregulation of MHC class I and class II molecules. Functional analysis showed that CMV-infected mature DCs suppress T-cell proliferation. Further FACS analysis demonstrated an upregulation of TRAIL (<a href="/entry/603598">603598</a>) and FASL, molecules that induce T-cell apoptosis through caspase (see CASP8; <a href="/entry/601763">601763</a>)-dependent mechanisms, on DCs. <a href="#17" class="mim-tip-reference" title="Raftery, M. J., Schwab, M., Eibert, S. M., Samstag, Y., Walczak, H., Schonrich, G. <strong>Targeting the function of mature dendritic cells by human cytomegalovirus: a multilayered viral defense strategy.</strong> Immunity 15: 997-1009, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11754820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11754820</a>] [<a href="https://doi.org/10.1016/s1074-7613(01)00239-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11754820">Raftery et al. (2001)</a> concluded that CMV evades the immune response by first downregulating MHC antigens, thereby diminishing T-cell responses, followed by an upregulation of apoptosis-inducing ligands that delete activated T cells. They also proposed that nondeletional, possibly cytokine-mediated mechanisms are involved in T-cell suppression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11754820" 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 GST pull-down analysis, <a href="#6" class="mim-tip-reference" title="Ghadimi, M. P., Sanzenbacher, R., Thiede, B., Wenzel, J., Jing, Q., Plomann, M., Borkhardt, A., Kabelitz, D., Janssen, O. <strong>Identification of interaction partners of the cytosolic polyproline region of CD95 ligand (CD178).</strong> FEBS Lett. 519: 50-58, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12023017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12023017</a>] [<a href="https://doi.org/10.1016/s0014-5793(02)02709-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12023017">Ghadimi et al. (2002)</a> showed that the C-terminal SH3 domains of GRB2 (<a href="/entry/108355">108355</a>), FBP17 (<a href="/entry/606191">606191</a>), and PACSIN2 (<a href="/entry/604960">604960</a>), as well as other related proteins, bind to the polyproline-rich region of the cytoplasmic tail of FASL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12023017" 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>Natural inhibitors of angiogenesis are able to block pathologic neovascularization without harming the preexisting vasculature. <a href="#26" class="mim-tip-reference" title="Volpert, O. V., Zaichuk, T., Zhou, W., Reiher, F., Ferguson, T. A., Stuart, P. M., Amin, M., Bouck, N. P. <strong>Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor.</strong> Nature Med. 8: 349-357, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11927940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11927940</a>] [<a href="https://doi.org/10.1038/nm0402-349" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11927940">Volpert et al. (2002)</a> demonstrated that 2 such inhibitors, thrombospondin I (<a href="/entry/188060">188060</a>) and pigment epithelium-derived factor (<a href="/entry/172860">172860</a>), derive specificity for remodeling vessels from their dependence on Fas/FasL-mediated apoptosis to block angiogenesis. Both inhibitors upregulated FasL on endothelial cells. Expression of the essential partner of FasL, Fas receptor, was low on quiescent endothelial cells and vessels but greatly enhanced by inducers of angiogenesis, thereby specifically sensitizing the stimulated cells to apoptosis by inhibitor-generated FasL. The antiangiogenic activity of thrombospondin I and pigment epithelium-derived factor both in vitro and in vivo was dependent on this dual induction of Fas and FasL and the resulting apoptosis. <a href="#26" class="mim-tip-reference" title="Volpert, O. V., Zaichuk, T., Zhou, W., Reiher, F., Ferguson, T. A., Stuart, P. M., Amin, M., Bouck, N. P. <strong>Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor.</strong> Nature Med. 8: 349-357, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11927940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11927940</a>] [<a href="https://doi.org/10.1038/nm0402-349" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11927940">Volpert et al. (2002)</a> concluded that this example of cooperation between pro- and antiangiogenic factors in the inhibition of angiogenesis provides one explanation for the ability of inhibitors to select remodeling capillaries for destruction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11927940" 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 quantitative immunostaining, <a href="#1" class="mim-tip-reference" title="Asanuma, K., Tsuji, N., Endoh, T., Yagihashi, A., Watanabe, N. <strong>Survivin enhances Fas ligand expression via up-regulation of specificity protein 1-mediated gene transcription in colon cancer cells.</strong> J. Immun. 172: 3922-3929, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15004200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15004200</a>] [<a href="https://doi.org/10.4049/jimmunol.172.6.3922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15004200">Asanuma et al. (2004)</a> found a correlation between expression of survivin (BIRC5; <a href="/entry/603352">603352</a>) and FASL in colon cancer tissues. Transfection of survivin into a colon cancer cell line upregulated FASL expression and increased cytotoxicity against a FAS-sensitive T-cell line. Transfected cells showed increased DNA binding of the transcription factor SP1 (<a href="/entry/189906">189906</a>) to the FASL promoter and upregulation of SP1 phosphorylation at ser and thr residues; the total amount of SP1 was not changed. Inhibition of survivin expression in a colon cancer cell line by small interfering RNA downregulated FASL expression. <a href="#1" class="mim-tip-reference" title="Asanuma, K., Tsuji, N., Endoh, T., Yagihashi, A., Watanabe, N. <strong>Survivin enhances Fas ligand expression via up-regulation of specificity protein 1-mediated gene transcription in colon cancer cells.</strong> J. Immun. 172: 3922-3929, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15004200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15004200</a>] [<a href="https://doi.org/10.4049/jimmunol.172.6.3922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15004200">Asanuma et al. (2004)</a> concluded that survivin enables cancer cells not only to suppress immune cell attack by inhibiting FAS-mediated apoptosis, but also to attack immune cells by induction of FASL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15004200" 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="Raoul, C., Buhler, E., Sadeghi, C., Jacquier, A., Aebischer, P., Pettmann, B., Henderson, C. E., Haase, G. <strong>Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL.</strong> Proc. Nat. Acad. Sci. 103: 6007-6012, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16581901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16581901</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16581901[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0508774103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16581901">Raoul et al. (2006)</a> reported that exogenous NO triggered expression of FASL in cultured motoneurons. In motoneurons from ALS (<a href="/entry/105400">105400</a>) model mice with mutations in the SOD1 gene (<a href="/entry/147450">147450</a>), this upregulation resulted in activation of Fas (<a href="/entry/134637">134637</a>), leading through Daxx (<a href="/entry/603186">603186</a>) and p38 (MAPK14; <a href="/entry/600289">600289</a>) to further NO synthesis. The authors suggested that chronic low-activation of this feedback loop may underlie the slowly progressive motoneuron loss characteristic of ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16581901" 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 flow cytometric analysis, <a href="#9" class="mim-tip-reference" title="Herbeuval, J.-P., Nilsson, J., Boasso, A., Hardy, A. W., Kruhlak, M. J., Anderson, S. A., Dolan, M. J., Dy, M., Andersson, J., Shearer, G. M. <strong>Differential expression of IFN-alpha and TRAIL/DR5 in lymphoid tissue of progressor versus nonprogressor HIV-1-infected patients.</strong> Proc. Nat. Acad. Sci. 103: 7000-7005, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16632604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16632604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16632604[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0600363103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16632604">Herbeuval et al. (2006)</a> found that human immunodeficiency virus (HIV)-positive patients had reduced circulating CD123 (<a href="/entry/308385">308385</a>)-positive plasmacytoid DCs in blood compared with HIV-negative controls. However, HIV-positive patients had higher secretion of IFNA (<a href="/entry/147660">147660</a>), higher cytoplasmic expression of MYD88 (<a href="/entry/602170">602170</a>) and IRF7 (<a href="/entry/605047">605047</a>), and higher surface expression of CCR7 (<a href="/entry/600242">600242</a>), suggesting migration of plasmacytoid DCs to lymph nodes. Immunohistochemical analysis showed high IFNA expression in T cell-rich areas of lymphoid tonsillar tissue of HIV-positive patients. RT-PCR analysis showed that expression of TRAIL and FASL, as well as that of their receptors, was significantly higher in lymphoid tonsillar tissue of patients with progressive HIV disease compared with patients with nonprogressive disease and HIV-negative controls, and TRAIL expression correlated with plasma viral load. <a href="#9" class="mim-tip-reference" title="Herbeuval, J.-P., Nilsson, J., Boasso, A., Hardy, A. W., Kruhlak, M. J., Anderson, S. A., Dolan, M. J., Dy, M., Andersson, J., Shearer, G. M. <strong>Differential expression of IFN-alpha and TRAIL/DR5 in lymphoid tissue of progressor versus nonprogressor HIV-1-infected patients.</strong> Proc. Nat. Acad. Sci. 103: 7000-7005, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16632604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16632604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16632604[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0600363103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16632604">Herbeuval et al. (2006)</a> concluded that the TRAIL and FASL apoptotic pathways are activated in more advanced HIV disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16632604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Nakamura, T., Imai, Y., Matsumoto, T., Sato, S., Takeuchi, K., Igarashi, K., Harada, Y., Azuma, Y., Krust, A., Yamamoto, Y., Nishina, H., Takeda, S., Takayanagi, H., Metzger, D., Kanno, J., Takaoka, K., Martin, T. J., Chambon, P., Kato, S. <strong>Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts.</strong> Cell 130: 811-823, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17803905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17803905</a>] [<a href="https://doi.org/10.1016/j.cell.2007.07.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17803905">Nakamura et al. (2007)</a> conditionally deleted estrogen receptor-1 (ESR1; <a href="/entry/133430">133430</a>) in adult mouse osteoclasts and showed that the protective effect of estrogen on bone in females involved upregulation of Fasl in osteoclasts of trabecular bone. They concluded that estrogen regulates the life span of mature osteoclasts via induction of the FAS/FASL system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17803905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Villa-Morales, M., Santos, J., Perez-Gomez, E., Quintanilla, M., Fernandez-Piqueras, J. <strong>A role for the Fas/FasL system in modulating genetic susceptibility to T-cell lymphoblastic lymphomas.</strong> Cancer Res. 67: 5107-5116, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17545588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17545588</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-06-4006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17545588">Villa-Morales et al. (2007)</a> found that expression of Fasl increased early in 2 mouse strains after gamma irradiation and was maintained at high levels for a long time in the strain that resisted tumor development. However, Fasl expression was practically absent in T-cell lymphoblastic lymphomas. <a href="#25" class="mim-tip-reference" title="Villa-Morales, M., Santos, J., Perez-Gomez, E., Quintanilla, M., Fernandez-Piqueras, J. <strong>A role for the Fas/FasL system in modulating genetic susceptibility to T-cell lymphoblastic lymphomas.</strong> Cancer Res. 67: 5107-5116, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17545588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17545588</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-06-4006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17545588">Villa-Morales et al. (2007)</a> identified functional polymorphisms in the Fasl promoter between the 2 mouse strains exhibiting distinct levels of Fasl expression and tumor susceptibility. In addition, several functional nucleotide changes in the coding sequences of both Fas and Fasl significantly affected their biologic activities. <a href="#25" class="mim-tip-reference" title="Villa-Morales, M., Santos, J., Perez-Gomez, E., Quintanilla, M., Fernandez-Piqueras, J. <strong>A role for the Fas/FasL system in modulating genetic susceptibility to T-cell lymphoblastic lymphomas.</strong> Cancer Res. 67: 5107-5116, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17545588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17545588</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-06-4006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17545588">Villa-Morales et al. (2007)</a> concluded that polymorphisms affecting either the expression or biologic activities of FAS or FASL may contribute to the genetic risk of developing T-cell lymphoblastic lymphomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17545588" 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>The pathogenesis of systemic lupus erythematosus (SLE; <a href="/entry/152700">152700</a>) is multifactorial and polygenic. The apoptosis genes FAS and FASL are candidate contributory genes in SLE, as mutations of these genes result in autoimmunity in several murine models of SLE. In humans, FAS mutations result in autoimmune lymphoproliferative syndrome, or ALPS (e.g., <a href="/entry/134637#0001">134637.0001</a>). <a href="#27" class="mim-tip-reference" title="Wu, J., Wilson, J., He, J., Xiang, L., Schur, P. H., Mountz, J. D. <strong>Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease.</strong> J. Clin. Invest. 98: 1107-1113, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8787672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8787672</a>] [<a href="https://doi.org/10.1172/JCI118892" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8787672">Wu et al. (1996)</a> screened DNA from 75 patients with SLE by SSCP analysis for potential mutations of the extracellular domain of FASL. A heterozygous SSCP anomaly for FASL was identified in 1 SLE patient who exhibited lymphoadenopathy. Molecular cloning and sequencing indicated that the genomic DNA of this patient contained a heterozygous 84-bp deletion within exon 4 of the FASL gene, resulting in a predicted 28-amino acid in-frame deletion (<a href="#0001">134638.0001</a>). A study of peripheral blood mononuclear cells from this patient revealed decreased FASL activity, decreased activation-induced cell death, and increased T-cell proliferation after activation. <a href="#12" class="mim-tip-reference" title="Lenardo, M. J. <strong>Personal Communication.</strong> Bethesda, Md. 1/14/1999."None>Lenardo (1999)</a> expressed the opinion that although this patient satisfied the rheumatologic criteria for a diagnosis of SLE, the features were more consistent with ALPS. This might be referred to as ALPS2 or ALPS1B, the form caused by mutations in the FAS gene being designated ALPS1A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8787672" 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="#28" class="mim-tip-reference" title="Zhang, X., Miao, X., Sun, T., Tan, W., Qu, S., Xiong, P., Zhou, Y., Lin, D. <strong>Functional polymorphisms in cell death pathway genes FAS and FASL contribute to the risk of lung cancer.</strong> J. Med. Genet. 42: 479-484, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15937082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15937082</a>] [<a href="https://doi.org/10.1136/jmg.2004.030106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15937082">Zhang et al. (2005)</a> genotyped 1,000 Han Chinese lung cancer (<a href="/entry/211980">211980</a>) patients and 1,270 controls for 2 functional polymorphisms in the promoter regions of the FAS and FASL genes, -1377G-A (<a href="/entry/134637#0021">134637.0021</a>) and -844T-C (<a href="#0002">134638.0002</a>), respectively. Compared to noncarriers, there was an increased risk of developing lung cancer for carriers of either the FAS -1377AA or the FASL -844CC genotype; carriers of both homozygous genotypes had a more than 4-fold increased risk. <a href="#28" class="mim-tip-reference" title="Zhang, X., Miao, X., Sun, T., Tan, W., Qu, S., Xiong, P., Zhou, Y., Lin, D. <strong>Functional polymorphisms in cell death pathway genes FAS and FASL contribute to the risk of lung cancer.</strong> J. Med. Genet. 42: 479-484, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15937082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15937082</a>] [<a href="https://doi.org/10.1136/jmg.2004.030106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15937082">Zhang et al. (2005)</a> stated that these results support the hypothesis that the FAS- and FASL-triggered apoptosis pathway plays an important role in human carcinogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15937082" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Sun, T., Zhou, Y., Li, H., Han, X., Shi, Y., Wang, L., Miao, X., Tan, W., Zhao, D., Zhang, X., Guo, Y., Lin, D. <strong>FASL -844C polymorphism is associated with increased activation-induced T cell death and risk of cervical cancer.</strong> J. Exp. Med. 202: 967-974, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16186185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16186185</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16186185[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20050707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16186185">Sun et al. (2005)</a> found that the FAS variants -670A and -1377G and the FASL variant -844T were expressed more highly on stimulated T cells than were the FAS -670G and -1377A variants or the FASL -844C variant. T cells carrying the FASL -844C allele exhibited increased activation-induced cell death. A case-control study of Han Chinese women in Beijing showed a statistically significant 3-fold increased risk of cervical cancer in FASL -844CC homozygotes compared with -844TT homozygotes. A trend for somewhat increased susceptibility in -844CT heterozygotes was not statistically significant. <a href="#21" class="mim-tip-reference" title="Sun, T., Zhou, Y., Li, H., Han, X., Shi, Y., Wang, L., Miao, X., Tan, W., Zhao, D., Zhang, X., Guo, Y., Lin, D. <strong>FASL -844C polymorphism is associated with increased activation-induced T cell death and risk of cervical cancer.</strong> J. Exp. Med. 202: 967-974, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16186185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16186185</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16186185[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20050707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16186185">Sun et al. (2005)</a> proposed that polymorphisms in the FAS-FASL pathway confer host susceptibility to cervical cancers, possibly caused by tumor cells escaping effector T cells due to enhanced activation-induced cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16186185" 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>Mice instilled with silica develop severe pulmonary inflammation with local production of TNFA and interstitial neutrophil and macrophage infiltration in the lungs, a phenotype that resembles silicosis, an industrial era disease that afflicts certain mining professions. <a href="#3" class="mim-tip-reference" title="Borges, V. M., Falcao, H., Leite-Junior, J. H., Alvim, L., Teixeira, G. P., Russo, M., Nobrega, A. F., Lopes, M. F., Rocco, P. M., Davidson, W. F., Linden, R., Yagita, H., Zin, W. A., DosReis, G. A. <strong>Fas ligand triggers pulmonary silicosis.</strong> J. Exp. Med. 194: 155-163, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11457890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11457890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11457890[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.194.2.155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11457890">Borges et al. (2001)</a> found that Fasl-deficient gld mice had reduced neutrophil extravasation into the bronchoalveolar space, did not show TNFA production increases, and did not have pulmonary inflammation in response to silica. Silica induced deferoxamine-inhibitable Fasl expression in wildtype lung macrophages in vivo and in vitro, as well as apoptosis of pulmonary macrophages. Analysis of bone marrow chimeras and local adoptive transfer experiments demonstrated that wildtype but not Fasl-deficient lung macrophages recruited neutrophils and initiated silicosis. The induction of silicosis could be blocked by the administration of neutralizing anti-Fasl antibodies. <a href="#3" class="mim-tip-reference" title="Borges, V. M., Falcao, H., Leite-Junior, J. H., Alvim, L., Teixeira, G. P., Russo, M., Nobrega, A. F., Lopes, M. F., Rocco, P. M., Davidson, W. F., Linden, R., Yagita, H., Zin, W. A., DosReis, G. A. <strong>Fas ligand triggers pulmonary silicosis.</strong> J. Exp. Med. 194: 155-163, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11457890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11457890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11457890[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.194.2.155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11457890">Borges et al. (2001)</a> proposed that apoptotic cell death is required for neutrophil extravasation and pulmonary inflammation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11457890" 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 mice with induced spinal cord injury, <a href="#5" class="mim-tip-reference" title="Demjen, D., Klussmann, S., Kleber, S., Zuliani, C., Stieltjes, B., Metzger, C., Hirt, U. A., Walczak, H., Falk, W., Essig, M., Edler, L., Krammer, P. H., Martin-Villalba, A. <strong>Neutralization of CD95 ligand promotes regeneration and functional recovery after spinal cord injury.</strong> Nature Med. 10: 389-395, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15004554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15004554</a>] [<a href="https://doi.org/10.1038/nm1007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15004554">Demjen et al. (2004)</a> found that antibody neutralization of CD95 ligand, but not of TNF, significantly decreased apoptotic cell death in the spinal cord as indicated by increased survival of oligodendrocytes, increased markers of axonal growth, and a corresponding increase in locomotor performance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15004554" 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="Ma, Y., Liu, H., Tu-Rapp, H., Thiesen, H.-J., Ibrahim, S. M., Cole, S. M., Pope, R. M. <strong>Fas ligation on macrophages enhances IL-1R1-Toll-like receptor 4 signaling and promotes chronic inflammation.</strong> Nature Immun. 5: 380-387, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15004557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15004557</a>] [<a href="https://doi.org/10.1038/ni1054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15004557">Ma et al. (2004)</a> observed that Fas-deficient (lpr/lpr) mice had less severe collagen-induced arthritis, but higher levels of Il1b (<a href="/entry/147720">147720</a>) in joints, than control mice, suggesting inefficient activation through Il1r1 (<a href="/entry/147810">147810</a>). Fas- and Fasl-deficient mouse macrophages and human macrophages treated with an antagonistic FASL antibody had suppressed NFKB (see <a href="/entry/164011">164011</a>) activation and cytokine production in response to IL1B or lipopolysaccharide. Ectopic expression of FADD (<a href="/entry/602457">602457</a>) or dominant-negative FADD (containing the death domain only) suppressed MYD88 (<a href="/entry/602170">602170</a>)-induced NFKB and IL6 (<a href="/entry/147620">147620</a>) promoter activation and cytokine expression. <a href="#13" class="mim-tip-reference" title="Ma, Y., Liu, H., Tu-Rapp, H., Thiesen, H.-J., Ibrahim, S. M., Cole, S. M., Pope, R. M. <strong>Fas ligation on macrophages enhances IL-1R1-Toll-like receptor 4 signaling and promotes chronic inflammation.</strong> Nature Immun. 5: 380-387, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15004557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15004557</a>] [<a href="https://doi.org/10.1038/ni1054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15004557">Ma et al. (2004)</a> concluded that the FAS-FASL interaction enhances activation through the IL1R1 or TLR4 (<a href="/entry/603030">603030</a>) pathway, possibly contributing to the pathogenesis of chronic arthritis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15004557" 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="#11" class="mim-tip-reference" title="Karray, S., Kress, C., Cuvellier, S., Hue-Beauvais, C., Damotte, D., Babinet, C., Levi-Strauss, M. <strong>Complete loss of Fas ligand gene causes massive lymphoproliferation and early death, indicating a residual activity of gld allele.</strong> J. Immun. 172: 2118-2125, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14764677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14764677</a>] [<a href="https://doi.org/10.4049/jimmunol.172.4.2118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14764677">Karray et al. (2004)</a> used Cre-loxP technology to conditionally induce Fasl-deficient mice. Fasl -/- mice showed normal fecundity, but they developed splenomegaly and lymphadenopathy with lymphocytic infiltration into multiple organs and autoimmune disease in an age-dependent manner. The splenomegaly and lymphadenopathy of Fasl -/- mice were accelerated and more pronounced than in gld mice. More than 50% of Fasl -/- mice died by 4 months of age. Killing of Fas-transfected target cells by Fasl -/- splenocytes was significantly lower than that mediated by gld mice, which were also severely impaired in this function. <a href="#11" class="mim-tip-reference" title="Karray, S., Kress, C., Cuvellier, S., Hue-Beauvais, C., Damotte, D., Babinet, C., Levi-Strauss, M. <strong>Complete loss of Fas ligand gene causes massive lymphoproliferation and early death, indicating a residual activity of gld allele.</strong> J. Immun. 172: 2118-2125, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14764677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14764677</a>] [<a href="https://doi.org/10.4049/jimmunol.172.4.2118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14764677">Karray et al. (2004)</a> proposed that the Fasl allele of gld mice may encode a protein still able to bind, albeit weakly, to the Fas receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14764677" 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="O'Reilly, L. A., Tai, L., Lee, L., Kruse, E. A., Grabow, S., Fairlie, W. D., Haynes, N. M., Tarlinton, D. M., Zhang, J.-G., Belz, G. T., Smyth, M. J., Bouillet, P., Robb, L., Strasser, A. <strong>Membrane-bound Fas ligand only is essential for Fas-induced apoptosis.</strong> Nature 461: 659-663, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19794494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19794494</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19794494[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19794494">O'Reilly et al. (2009)</a> generated gene-targeted mice that selectively lack either secreted FasL (sFasL) or membrane-bound FasL (mFasL) to resolve which of these forms is required for cell killing and to explore their hypothesized nonapoptotic activities. Mice lacking sFasL appeared normal and their T cells readily killed target cells, whereas T cells lacking mFasL could not kill cells through Fas activation. Mice deficient in mFasL developed lymphadenopathy and hypergammaglobulinemia, similar to FasL (gld/gld) mice, which express a mutant form of FasL that cannot bind Fas, but surprisingly, mFasL-deficient mice (on a C57BL/6 background) succumbed to SLE (<a href="/entry/152700">152700</a>)-like autoimmune kidney destruction and histiocytic sarcoma, diseases that occur only rarely and much later in the FasL(gld/gld) mice. <a href="#15" class="mim-tip-reference" title="O'Reilly, L. A., Tai, L., Lee, L., Kruse, E. A., Grabow, S., Fairlie, W. D., Haynes, N. M., Tarlinton, D. M., Zhang, J.-G., Belz, G. T., Smyth, M. J., Bouillet, P., Robb, L., Strasser, A. <strong>Membrane-bound Fas ligand only is essential for Fas-induced apoptosis.</strong> Nature 461: 659-663, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19794494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19794494</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19794494[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19794494">O'Reilly et al. (2009)</a> concluded that mFasL is essential for cytotoxic activity and constitutes the guardian against lymphadenopathy, autoimmunity, and cancer, whereas excess sFasL appears to promote autoimmunity and tumorigenesis through nonapoptotic activities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19794494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>2 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=134638[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 AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IB</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80358236 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80358236;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=rs80358236" 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=rs80358236" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000017959 OR RCV001789750" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017959, RCV001789750" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017959...</a>
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<p>In a patient with SLE (<a href="/entry/152700">152700</a>) who exhibited lymphadenopathy, <a href="#27" class="mim-tip-reference" title="Wu, J., Wilson, J., He, J., Xiang, L., Schur, P. H., Mountz, J. D. <strong>Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease.</strong> J. Clin. Invest. 98: 1107-1113, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8787672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8787672</a>] [<a href="https://doi.org/10.1172/JCI118892" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8787672">Wu et al. (1996)</a> identified a heterozygous 84-bp deletion within exon 4 of the FASL gene, resulting in a predicted 28-amino acid in-frame deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8787672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Lenardo, M. J. <strong>Personal Communication.</strong> Bethesda, Md. 1/14/1999."None>Lenardo (1999)</a> suggested that this patient should be classified as having autoimmune lymphoproliferative syndrome (<a href="/entry/601859">601859</a>) due to mutation in the FASL gene. This form of ALPS has been designated ALPS1B, the form due to mutation in the FAS gene being ALPS1A.</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> rs763110 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs763110;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/rs763110?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=rs763110" 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=rs763110" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000017960" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017960" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017960</a>
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<p><a href="#28" class="mim-tip-reference" title="Zhang, X., Miao, X., Sun, T., Tan, W., Qu, S., Xiong, P., Zhou, Y., Lin, D. <strong>Functional polymorphisms in cell death pathway genes FAS and FASL contribute to the risk of lung cancer.</strong> J. Med. Genet. 42: 479-484, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15937082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15937082</a>] [<a href="https://doi.org/10.1136/jmg.2004.030106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15937082">Zhang et al. (2005)</a> genotyped 1,000 Han Chinese lung cancer (<a href="/entry/211980">211980</a>) patients and 1,270 controls for 2 functional polymorphisms in the promoter regions of the FAS and FASL genes, -1377G-A (<a href="/entry/134637#0021">134637.0021</a>) and -844T-C, respectively. Compared to noncarriers, there was a 1.6-fold increased risk of developing lung cancer for carriers of the FAS -1377AA genotype and a 1.8-fold increased risk for carriers of the FASL -844CC genotype. Carriers of both homozygous genotypes had a more than 4-fold increased risk, indicative of multiplicative gene-gene interaction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15937082" 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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Asanuma, K., Tsuji, N., Endoh, T., Yagihashi, A., Watanabe, N.
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<strong>Survivin enhances Fas ligand expression via up-regulation of specificity protein 1-mediated gene transcription in colon cancer cells.</strong>
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J. Immun. 172: 3922-3929, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15004200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15004200</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15004200" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.4049/jimmunol.172.6.3922" target="_blank">Full Text</a>]
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Bellgrau, D., Gold, D., Selawry, H., Moore, J., Franzusoff, A., Duke, R. C.
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<strong>A role for CD95 ligand in preventing graft rejection.</strong>
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Nature 377: 630-632, 1995. Note: Erratum: Nature 394: 133 only, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7566174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7566174</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7566174" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/377630a0" target="_blank">Full Text</a>]
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Borges, V. M., Falcao, H., Leite-Junior, J. H., Alvim, L., Teixeira, G. P., Russo, M., Nobrega, A. F., Lopes, M. F., Rocco, P. M., Davidson, W. F., Linden, R., Yagita, H., Zin, W. A., DosReis, G. A.
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<strong>Fas ligand triggers pulmonary silicosis.</strong>
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J. Exp. Med. 194: 155-163, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11457890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11457890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11457890[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11457890" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1084/jem.194.2.155" target="_blank">Full Text</a>]
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D'Alessio, A., Riccioli, A., Lauretti, P., Padula, F., Muciaccia, B., De Cesaris, P., Filippini, A., Nagata, S., Ziparo, E.
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<strong>Testicular FasL is expressed by sperm cells.</strong>
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Proc. Nat. Acad. Sci. 98: 3316-3321, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11248076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11248076</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11248076[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11248076" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16186185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16186185</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16186185[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16186185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1084/jem.20050707" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Takahashi1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Takahashi, T., Tanaka, M., Brannan, C. I., Jenkins, N. A., Copeland, N. G., Suda, T., Nagata, S.
|
|
<strong>Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand.</strong>
|
|
Cell 76: 969-976, 1994.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7511063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7511063</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7511063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0092-8674(94)90375-1" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Takahashi1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
|
Takahashi, T., Tanaka, M., Inazawa, J., Abe, T., Suda, T., Nagata, S.
|
|
<strong>Human Fas ligand: gene structure, chromosomal location and species specificity.</strong>
|
|
Int. Immun. 6: 1567-1574, 1994.
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|
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|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7826947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7826947</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7826947" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/intimm/6.10.1567" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Viard1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Viard, I., Wehrli, P., Bullani, R., Schneider, P., Holler, N., Salomon, D., Hunziker, T., Saurat, J.-H., Tschopp, J., French, L. E.
|
|
<strong>Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin.</strong>
|
|
Science 282: 490-493, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774279</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9774279" 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.282.5388.490" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="Villa-Morales2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Villa-Morales, M., Santos, J., Perez-Gomez, E., Quintanilla, M., Fernandez-Piqueras, J.
|
|
<strong>A role for the Fas/FasL system in modulating genetic susceptibility to T-cell lymphoblastic lymphomas.</strong>
|
|
Cancer Res. 67: 5107-5116, 2007.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17545588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17545588</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17545588" 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/10.1158/0008-5472.CAN-06-4006" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Volpert2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Volpert, O. V., Zaichuk, T., Zhou, W., Reiher, F., Ferguson, T. A., Stuart, P. M., Amin, M., Bouck, N. P.
|
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<strong>Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor.</strong>
|
|
Nature Med. 8: 349-357, 2002.
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|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11927940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11927940</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11927940" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nm0402-349" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Wu1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wu, J., Wilson, J., He, J., Xiang, L., Schur, P. H., Mountz, J. D.
|
|
<strong>Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease.</strong>
|
|
J. Clin. Invest. 98: 1107-1113, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8787672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8787672</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8787672" 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/10.1172/JCI118892" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="28" class="mim-anchor"></a>
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<a id="Zhang2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, X., Miao, X., Sun, T., Tan, W., Qu, S., Xiong, P., Zhou, Y., Lin, D.
|
|
<strong>Functional polymorphisms in cell death pathway genes FAS and FASL contribute to the risk of lung cancer.</strong>
|
|
J. Med. Genet. 42: 479-484, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15937082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15937082</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15937082" 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/10.1136/jmg.2004.030106" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 11/16/2009
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse - updated : 8/20/2008<br>Patricia A. Hartz - updated : 3/4/2008<br>Patricia A. Hartz - updated : 2/7/2008<br>Paul J. Converse - updated : 6/19/2006<br>Cassandra L. Kniffin - updated : 6/2/2006<br>Paul J. Converse - updated : 11/8/2005<br>Marla J. F. O'Neill - updated : 7/21/2005<br>Paul J. Converse - updated : 8/11/2004<br>Paul J. Converse - updated : 4/19/2004<br>Cassandra L. Kniffin - updated : 3/12/2004<br>Paul J. Converse - updated : 5/29/2002<br>Ada Hamosh - updated : 4/9/2002<br>Paul J. Converse - updated : 2/25/2002<br>Paul J. Converse - updated : 10/4/2001<br>Victor A. McKusick - updated : 4/11/2001<br>Ada Hamosh - updated : 10/30/2000<br>Ada Hamosh - updated : 8/5/1999<br>Ada Hamosh - updated : 5/13/1999<br>Victor A. McKusick - updated : 2/3/1999<br>Ada Hamosh - updated : 10/15/1998<br>Victor A. McKusick - updated : 3/16/1997
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 4/12/1994
|
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/27/2025
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 11/11/2014<br>carol : 4/3/2013<br>carol : 2/6/2012<br>alopez : 11/20/2009<br>alopez : 11/18/2009<br>terry : 11/16/2009<br>terry : 11/16/2009<br>mgross : 8/28/2008<br>terry : 8/20/2008<br>mgross : 3/4/2008<br>mgross : 2/8/2008<br>mgross : 2/8/2008<br>terry : 2/7/2008<br>mgross : 6/19/2006<br>wwang : 6/2/2006<br>mgross : 11/8/2005<br>wwang : 10/27/2005<br>wwang : 7/25/2005<br>terry : 7/21/2005<br>carol : 11/17/2004<br>ckniffin : 11/2/2004<br>mgross : 8/11/2004<br>mgross : 8/11/2004<br>carol : 5/25/2004<br>mgross : 4/19/2004<br>alopez : 4/13/2004<br>alopez : 4/2/2004<br>ckniffin : 3/12/2004<br>mgross : 5/29/2002<br>cwells : 4/17/2002<br>cwells : 4/15/2002<br>cwells : 4/12/2002<br>terry : 4/9/2002<br>mgross : 2/25/2002<br>mgross : 2/25/2002<br>mcapotos : 10/4/2001<br>mgross : 10/4/2001<br>alopez : 5/10/2001<br>mcapotos : 4/18/2001<br>mcapotos : 4/12/2001<br>terry : 4/11/2001<br>mgross : 10/30/2000<br>alopez : 10/11/2000<br>alopez : 8/5/1999<br>alopez : 5/13/1999<br>terry : 5/13/1999<br>mgross : 5/10/1999<br>mgross : 5/10/1999<br>terry : 5/3/1999<br>carol : 2/8/1999<br>terry : 2/3/1999<br>alopez : 12/21/1998<br>alopez : 10/15/1998<br>terry : 5/29/1998<br>alopez : 3/16/1998<br>alopez : 3/16/1998<br>terry : 2/25/1998<br>terry : 2/25/1998<br>alopez : 7/29/1997<br>alopez : 7/7/1997<br>mark : 6/14/1997<br>mark : 3/16/1997<br>terry : 3/10/1997<br>mark : 2/23/1997<br>terry : 11/26/1996<br>mark : 10/17/1996<br>mark : 10/9/1996<br>mark : 12/13/1995<br>mark : 10/18/1995<br>warfield : 4/20/1994<br>carol : 4/12/1994
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
|
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<strong>*</strong> 134638
|
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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FAS LIGAND; FASLG
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
|
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
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</span>
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</p>
|
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
FASL<br />
|
|
TUMOR NECROSIS FACTOR LIGAND SUPERFAMILY, MEMBER 6; TNFSF6<br />
|
|
APOPTOSIS ANTIGEN LIGAND 1; APT1LG1<br />
|
|
APOPTOSIS ANTIGEN LIGAND<br />
|
|
CD95 LIGAND; CD95L<br />
|
|
CD178 ANTIGEN; CD178
|
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</span>
|
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: FASLG</em></strong>
|
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong>
|
|
<em>
|
|
Cytogenetic location: 1q24.3
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 1:172,659,103-172,666,876 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
1q24.3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Lung cancer, susceptibility to}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
211980
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Somatic mutation
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
Autoimmune lymphoproliferative syndrome, type IB
|
|
</span>
|
|
</td>
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<span class="mim-font">
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601859
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<span class="mim-font">
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Autosomal dominant
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</span>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Life requires death. Elimination of unwanted cells is vital for embryogenesis, metamorphosis and tissue turnover, as well as for the development and function of the immune system. Mammalian development is tightly regulated not only by the proliferation and differentiation of cells but also by cell death. The cell death that occurs during development or tissue turnover is called programmed cell death, most of which proceeds via apoptosis. Apoptosis is morphologically distinguished from necrosis, which occurs during the accidental cell death caused by physical or chemical agents. During apoptosis, the cytoplasm of the affected cells condenses, and the nucleus also condenses and becomes fragmented. At the final stage of apoptosis, the cells themselves are fragmented (apoptotic bodies) and are phagocytosed by neighboring macrophages and granulocytes. Apoptosis occurs not only during programmed cell death, but also during the death process induced by some cytotoxic T cells. Suda et al. (1993) identified the ligand that triggers cell death by binding to the cell surface receptor variously known as FAS or APT1 (TNFRSF6; 134637). This cell surface receptor was discovered in 1989 with the isolation of 2 monoclonal antibodies (anti-Fas and anti-Apo-1) that had the startling property of killing a human cell line used as the immunogen. Cell death occurred by apoptosis. Cloning of the genes revealed that the antigens recognized by the 2 monoclonal antibodies were one and the same. It is a transmembrane protein related to a family of receptors that includes the 2 tumor necrosis factor (TNF) receptors (191190, 191191). In mice, mutations at the lpr (lymphoproliferation) locus have a defect in the FAS antigen. The inability of homozygous mutant mice to mediate FAS-induced apoptosis provokes a complex immunologic disorder featuring defects in both the B and T lymphoid compartments. A very similar phenotype of mice homozygous for the gld (generalized lymphoproliferative disease) mutation suggested that the gld gene encodes the ligand for FAS. Suda et al. (1993) isolated the ligand from a cytotoxic T hybridoma by a sensitive expression cloning strategy. The amino acid sequence indicated that FAS ligand is a type II transmembrane protein that belongs to the tumor necrosis factor family. Northern hybridization revealed that the ligand is expressed in activated splenocytes and thymocytes, consistent with its involvement in T cell-mediated cytotoxicity, and in several nonlymphoid tissues, such as testis. The FAS antigen is expressed not only in the cells of the immune system but also in the liver, lung, ovary, and heart, where its function was unclear. </p><p>Takahashi et al. (1994) isolated the chromosomal gene for human FasL. The human FASL cDNA predicted a type II membrane protein consisting of 281 amino acids and a calculated M(r) of 31,759 that showed 76.9% amino acid sequence identity with the mouse protein. When expressed in COS cells, both human and mouse recombinant FasL induced apoptosis, indicating crossreactivity. A sequence of approximately 300 bp upstream of the ATG initiation codon was found to be highly conserved between mouse and human. Several transcription cis-regulatory elements such as SP1 (189906), NF-kappa-B (see 164011), and IRF1 (147575) were recognized in this region. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</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>Takahashi et al. (1994) determined that the human FASL gene contains 4 exons and spans approximately 8 kb. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Takahashi et al. (1994) mapped the human FASL gene to chromosome 1q23 by fluorescence in situ hybridization. </p><p>By interspecific backcross analysis, Takahashi et al. (1994) localized the murine Fasl gene to the gld region of mouse chromosome 1. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Takahashi et al. (1994) isolated the murine Fasl gene and showed that activated splenocytes from 'generalized lymphoproliferative disease' (gld) mice express Fasl mRNA. However, the Fas ligand protein in gld mice carried a point mutation in the C-terminal region, which is highly conserved among members of the TNF family. Recombinant gld Fas ligand expressed in COS cells could not induce apoptosis in cells expressing Fas. </p><p>Testis is a remarkably immune-privileged site, long known for its ability to support allogeneic and xenogeneic tissue transplants. Bellgrau et al. (1995) reported results suggesting that expression of FasL by Sertoli cells accounts for the immune-privileged nature of testis. Testis grafts derived from mice that can express functional FasL survived indefinitely when transplanted under the kidney capsule of allogeneic mice, whereas testis graft derived from mutant gld mice, which express nonfunctional ligand, were rejected. The authors speculated that FasL expression in the testis probably acts by inducing apoptotic cell death of Fas-expressing, recipient T cells activated in response to graft antigens. D'Alessio et al. (2001) demonstrated that the attribution of testicular expression of FasL to Sertoli cells is erroneous and that FasL transcription instead occurs in meiotic and postmeiotic germ cells, whereas the protein is only displayed on mature spermatozoa. These findings point to a significant role of the Fas system in the biology of mammalian reproduction. </p><p>Hahne et al. (1996) stated that, despite the existence of melanoma-specific cytolytic T cells in tumor-infiltrating lymphocytes and in peripheral blood from melanoma patients, and the definition of 12 CTL-defined melanoma peptide antigens, melanoma cells are able to avoid immune detection in most instances. The investigators proposed that FASL-expressing melanoma cells may kill FAS (134637)-sensitive activating T lymphocytes. They analyzed FASL expression in melanoma cells and demonstrated substantial quantities of FASL in lysates of a series of human melanoma cells. Two molecular species were identified: a 40-kD membrane-bound FASL and a 27-kD extracellular FASL. Hahne et al. (1996) also demonstrated that the majority of cells infiltrating the tumors were FAS-positive. No FASL was found in normal melanocytes of the skin, suggesting that FASL upregulation occurs during tumorigenesis. Hahne et al. (1996) proposed that FASL-expressing melanoma cells might induce apoptosis of FAS-sensitive tumor infiltrating cells. They reported that injection of FasL+ mouse melanoma cells in mice led to rapid tumor formation. When FasL+ mouse melanoma cells were injected into FAS-deficient mutant mice, tumorigenesis was delayed. These findings led Hahne et al. (1996) to conclude that FASL may contribute to the immune privilege of tumors. They proposed further that pharmacologic products that render infiltrating T cells insensitive to FASL-induced killing may break the immunologic unresponsiveness to melanoma and provide a complementary approach in the therapy of malignant melanoma. </p><p>In the United States more than 43,000 corneal transplants are performed each year, making it the most common form of solid tissue transplantation, and second only to bone marrow transplants in overall numbers performed. Corneal transplantation is also one of the most successful types of transplantation with failure rates at only 10 to 15% after 1 year and approximately 30% after 5 years. Stuart et al. (1997) demonstrated that the very high percentage of successful corneal transplants, without tissue matching or immunosuppressant therapy, is related to the expression of abundant functional FASL in the cornea, capable of killing FASL(+) lymphoid cells. Using a mouse model for corneal allograft transplantation, FasL(+) orthografts were accepted at a rate of 45%, whereas FasL(-) or normal grafts transplanted to Fas(-) mice were rejected 100% of the time. </p><p>Viard et al. (1998) detected high levels of soluble FASL in the sera of patients with toxic epidermal necrolysis (TEN; 608579). Keratinocytes of TEN patients produced FASL, which induced keratinic apoptosis. Incubating keratinocytes with intravenous immunoglobulin (IVIG) completely inhibited FAS-mediated keratinocyte apoptosis. A naturally occurring anti-FAS immunoglobulin present in IVIG blocks the FAS receptor and mediates this response. Ten patients with TEN were treated with IVIG. Progression of skin disease was rapidly reversed in all cases. </p><p>DNA-damaged cells can either repair the DNA or be eliminated through a homeostatic control mechanism mediated by p53 (191170) termed 'cellular proofreading.' Elimination of DNA-damaged cells after UV radiation through sunburn cell (or apoptotic keratinocyte) formation is thought to be pivotal for the removal of precancerous skin cells. Hill et al. (1999) demonstrated that sunburn cell formation is dependent upon FasL. Chronic exposure to UV radiation caused 14 of 20, or 70%, of FasL-deficient mice and 1 of 20, or 5%, of wildtype mice to accumulate p53 mutations in the epidermis. Hill et al. (1999) concluded that FASL-mediated apoptosis is important for skin homeostasis, suggesting that the dysregulation of FAS-FASL interactions may be central to the development of skin cancer. </p><p>Pestano et al. (1999) identified a differentiative pathway taken by CD8 cells bearing receptors that cannot engage class I MHC (see 142800) self-peptide molecules because of incorrect thymic selection, defects in peripheral MHC class I expression, or antigen presentation. In any of these cases, failed CD8 T-cell receptor coengagement results in downregulation of genes that account for specialized cytolytic T-lymphocyte function and resistance to cell death (CD8-alpha/beta, see 186730; granzyme B, 123910; and LKLF, 602016), and upregulation of Fas and FasL death genes. Thus, MHC engagement is required to inhibit expression and delivery of a death program rather than to supply a putative trophic factor for T cell survival. Pestano et al. (1999) hypothesized that defects in delivery of the death signal to these cells underlie the explosive growth and accumulation of double-negative T cells in animals bearing Fas and FasL mutations, in patients that carry inherited mutations of these genes, and in about 25% of systemic lupus erythematosus patients that display the cellular signature of defects in this mechanism of quality control of CD8 cells. </p><p>Grassme et al. (2000) showed that Pseudomonas aeruginosa infection induces apoptosis of lung epithelial cells by activation of the endogenous CD95/CD95L system. Deficiency of CD95 or CD95L on epithelial cells prevented apoptosis of lung epithelial cells in vivo as well as in vitro. The importance of CD95/CD95L-mediated lung epithelial cell apoptosis was demonstrated by the rapid development of sepsis in mice deficient in either CD95 or CD95L, but not in normal mice, after P. aeruginosa infection. </p><p>Cytomegalovirus (CMV) is a persistent viral pathogen that resides in monocyte/macrophages and dendritic cells (DCs), critical antigen-presenting cells in the immune system. In fetal and compromised immune systems, CMV can be fatal. Raftery et al. (2001) found that recent CMV isolates, but not fibroblast-adapted CMV strains, could infect mature DCs with no change in some cell surface markers. On the other hand, flow cytometric analysis indicated a slight upregulation of the costimulatory molecules CD40 (109535), CD80 (112203), and CD86 (601020), as well as a downregulation of MHC class I and class II molecules. Functional analysis showed that CMV-infected mature DCs suppress T-cell proliferation. Further FACS analysis demonstrated an upregulation of TRAIL (603598) and FASL, molecules that induce T-cell apoptosis through caspase (see CASP8; 601763)-dependent mechanisms, on DCs. Raftery et al. (2001) concluded that CMV evades the immune response by first downregulating MHC antigens, thereby diminishing T-cell responses, followed by an upregulation of apoptosis-inducing ligands that delete activated T cells. They also proposed that nondeletional, possibly cytokine-mediated mechanisms are involved in T-cell suppression. </p><p>Using GST pull-down analysis, Ghadimi et al. (2002) showed that the C-terminal SH3 domains of GRB2 (108355), FBP17 (606191), and PACSIN2 (604960), as well as other related proteins, bind to the polyproline-rich region of the cytoplasmic tail of FASL. </p><p>Natural inhibitors of angiogenesis are able to block pathologic neovascularization without harming the preexisting vasculature. Volpert et al. (2002) demonstrated that 2 such inhibitors, thrombospondin I (188060) and pigment epithelium-derived factor (172860), derive specificity for remodeling vessels from their dependence on Fas/FasL-mediated apoptosis to block angiogenesis. Both inhibitors upregulated FasL on endothelial cells. Expression of the essential partner of FasL, Fas receptor, was low on quiescent endothelial cells and vessels but greatly enhanced by inducers of angiogenesis, thereby specifically sensitizing the stimulated cells to apoptosis by inhibitor-generated FasL. The antiangiogenic activity of thrombospondin I and pigment epithelium-derived factor both in vitro and in vivo was dependent on this dual induction of Fas and FasL and the resulting apoptosis. Volpert et al. (2002) concluded that this example of cooperation between pro- and antiangiogenic factors in the inhibition of angiogenesis provides one explanation for the ability of inhibitors to select remodeling capillaries for destruction. </p><p>By quantitative immunostaining, Asanuma et al. (2004) found a correlation between expression of survivin (BIRC5; 603352) and FASL in colon cancer tissues. Transfection of survivin into a colon cancer cell line upregulated FASL expression and increased cytotoxicity against a FAS-sensitive T-cell line. Transfected cells showed increased DNA binding of the transcription factor SP1 (189906) to the FASL promoter and upregulation of SP1 phosphorylation at ser and thr residues; the total amount of SP1 was not changed. Inhibition of survivin expression in a colon cancer cell line by small interfering RNA downregulated FASL expression. Asanuma et al. (2004) concluded that survivin enables cancer cells not only to suppress immune cell attack by inhibiting FAS-mediated apoptosis, but also to attack immune cells by induction of FASL. </p><p>Raoul et al. (2006) reported that exogenous NO triggered expression of FASL in cultured motoneurons. In motoneurons from ALS (105400) model mice with mutations in the SOD1 gene (147450), this upregulation resulted in activation of Fas (134637), leading through Daxx (603186) and p38 (MAPK14; 600289) to further NO synthesis. The authors suggested that chronic low-activation of this feedback loop may underlie the slowly progressive motoneuron loss characteristic of ALS. </p><p>Using flow cytometric analysis, Herbeuval et al. (2006) found that human immunodeficiency virus (HIV)-positive patients had reduced circulating CD123 (308385)-positive plasmacytoid DCs in blood compared with HIV-negative controls. However, HIV-positive patients had higher secretion of IFNA (147660), higher cytoplasmic expression of MYD88 (602170) and IRF7 (605047), and higher surface expression of CCR7 (600242), suggesting migration of plasmacytoid DCs to lymph nodes. Immunohistochemical analysis showed high IFNA expression in T cell-rich areas of lymphoid tonsillar tissue of HIV-positive patients. RT-PCR analysis showed that expression of TRAIL and FASL, as well as that of their receptors, was significantly higher in lymphoid tonsillar tissue of patients with progressive HIV disease compared with patients with nonprogressive disease and HIV-negative controls, and TRAIL expression correlated with plasma viral load. Herbeuval et al. (2006) concluded that the TRAIL and FASL apoptotic pathways are activated in more advanced HIV disease. </p><p>Nakamura et al. (2007) conditionally deleted estrogen receptor-1 (ESR1; 133430) in adult mouse osteoclasts and showed that the protective effect of estrogen on bone in females involved upregulation of Fasl in osteoclasts of trabecular bone. They concluded that estrogen regulates the life span of mature osteoclasts via induction of the FAS/FASL system. </p><p>Villa-Morales et al. (2007) found that expression of Fasl increased early in 2 mouse strains after gamma irradiation and was maintained at high levels for a long time in the strain that resisted tumor development. However, Fasl expression was practically absent in T-cell lymphoblastic lymphomas. Villa-Morales et al. (2007) identified functional polymorphisms in the Fasl promoter between the 2 mouse strains exhibiting distinct levels of Fasl expression and tumor susceptibility. In addition, several functional nucleotide changes in the coding sequences of both Fas and Fasl significantly affected their biologic activities. Villa-Morales et al. (2007) concluded that polymorphisms affecting either the expression or biologic activities of FAS or FASL may contribute to the genetic risk of developing T-cell lymphoblastic lymphomas. </p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The pathogenesis of systemic lupus erythematosus (SLE; 152700) is multifactorial and polygenic. The apoptosis genes FAS and FASL are candidate contributory genes in SLE, as mutations of these genes result in autoimmunity in several murine models of SLE. In humans, FAS mutations result in autoimmune lymphoproliferative syndrome, or ALPS (e.g., 134637.0001). Wu et al. (1996) screened DNA from 75 patients with SLE by SSCP analysis for potential mutations of the extracellular domain of FASL. A heterozygous SSCP anomaly for FASL was identified in 1 SLE patient who exhibited lymphoadenopathy. Molecular cloning and sequencing indicated that the genomic DNA of this patient contained a heterozygous 84-bp deletion within exon 4 of the FASL gene, resulting in a predicted 28-amino acid in-frame deletion (134638.0001). A study of peripheral blood mononuclear cells from this patient revealed decreased FASL activity, decreased activation-induced cell death, and increased T-cell proliferation after activation. Lenardo (1999) expressed the opinion that although this patient satisfied the rheumatologic criteria for a diagnosis of SLE, the features were more consistent with ALPS. This might be referred to as ALPS2 or ALPS1B, the form caused by mutations in the FAS gene being designated ALPS1A. </p><p>Zhang et al. (2005) genotyped 1,000 Han Chinese lung cancer (211980) patients and 1,270 controls for 2 functional polymorphisms in the promoter regions of the FAS and FASL genes, -1377G-A (134637.0021) and -844T-C (134638.0002), respectively. Compared to noncarriers, there was an increased risk of developing lung cancer for carriers of either the FAS -1377AA or the FASL -844CC genotype; carriers of both homozygous genotypes had a more than 4-fold increased risk. Zhang et al. (2005) stated that these results support the hypothesis that the FAS- and FASL-triggered apoptosis pathway plays an important role in human carcinogenesis. </p><p>Sun et al. (2005) found that the FAS variants -670A and -1377G and the FASL variant -844T were expressed more highly on stimulated T cells than were the FAS -670G and -1377A variants or the FASL -844C variant. T cells carrying the FASL -844C allele exhibited increased activation-induced cell death. A case-control study of Han Chinese women in Beijing showed a statistically significant 3-fold increased risk of cervical cancer in FASL -844CC homozygotes compared with -844TT homozygotes. A trend for somewhat increased susceptibility in -844CT heterozygotes was not statistically significant. Sun et al. (2005) proposed that polymorphisms in the FAS-FASL pathway confer host susceptibility to cervical cancers, possibly caused by tumor cells escaping effector T cells due to enhanced activation-induced cell death. </p>
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</span>
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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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<span class="mim-text-font">
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<p>Mice instilled with silica develop severe pulmonary inflammation with local production of TNFA and interstitial neutrophil and macrophage infiltration in the lungs, a phenotype that resembles silicosis, an industrial era disease that afflicts certain mining professions. Borges et al. (2001) found that Fasl-deficient gld mice had reduced neutrophil extravasation into the bronchoalveolar space, did not show TNFA production increases, and did not have pulmonary inflammation in response to silica. Silica induced deferoxamine-inhibitable Fasl expression in wildtype lung macrophages in vivo and in vitro, as well as apoptosis of pulmonary macrophages. Analysis of bone marrow chimeras and local adoptive transfer experiments demonstrated that wildtype but not Fasl-deficient lung macrophages recruited neutrophils and initiated silicosis. The induction of silicosis could be blocked by the administration of neutralizing anti-Fasl antibodies. Borges et al. (2001) proposed that apoptotic cell death is required for neutrophil extravasation and pulmonary inflammation. </p><p>In mice with induced spinal cord injury, Demjen et al. (2004) found that antibody neutralization of CD95 ligand, but not of TNF, significantly decreased apoptotic cell death in the spinal cord as indicated by increased survival of oligodendrocytes, increased markers of axonal growth, and a corresponding increase in locomotor performance. </p><p>Ma et al. (2004) observed that Fas-deficient (lpr/lpr) mice had less severe collagen-induced arthritis, but higher levels of Il1b (147720) in joints, than control mice, suggesting inefficient activation through Il1r1 (147810). Fas- and Fasl-deficient mouse macrophages and human macrophages treated with an antagonistic FASL antibody had suppressed NFKB (see 164011) activation and cytokine production in response to IL1B or lipopolysaccharide. Ectopic expression of FADD (602457) or dominant-negative FADD (containing the death domain only) suppressed MYD88 (602170)-induced NFKB and IL6 (147620) promoter activation and cytokine expression. Ma et al. (2004) concluded that the FAS-FASL interaction enhances activation through the IL1R1 or TLR4 (603030) pathway, possibly contributing to the pathogenesis of chronic arthritis. </p><p>Karray et al. (2004) used Cre-loxP technology to conditionally induce Fasl-deficient mice. Fasl -/- mice showed normal fecundity, but they developed splenomegaly and lymphadenopathy with lymphocytic infiltration into multiple organs and autoimmune disease in an age-dependent manner. The splenomegaly and lymphadenopathy of Fasl -/- mice were accelerated and more pronounced than in gld mice. More than 50% of Fasl -/- mice died by 4 months of age. Killing of Fas-transfected target cells by Fasl -/- splenocytes was significantly lower than that mediated by gld mice, which were also severely impaired in this function. Karray et al. (2004) proposed that the Fasl allele of gld mice may encode a protein still able to bind, albeit weakly, to the Fas receptor. </p><p>O'Reilly et al. (2009) generated gene-targeted mice that selectively lack either secreted FasL (sFasL) or membrane-bound FasL (mFasL) to resolve which of these forms is required for cell killing and to explore their hypothesized nonapoptotic activities. Mice lacking sFasL appeared normal and their T cells readily killed target cells, whereas T cells lacking mFasL could not kill cells through Fas activation. Mice deficient in mFasL developed lymphadenopathy and hypergammaglobulinemia, similar to FasL (gld/gld) mice, which express a mutant form of FasL that cannot bind Fas, but surprisingly, mFasL-deficient mice (on a C57BL/6 background) succumbed to SLE (152700)-like autoimmune kidney destruction and histiocytic sarcoma, diseases that occur only rarely and much later in the FasL(gld/gld) mice. O'Reilly et al. (2009) concluded that mFasL is essential for cytotoxic activity and constitutes the guardian against lymphadenopathy, autoimmunity, and cancer, whereas excess sFasL appears to promote autoimmunity and tumorigenesis through nonapoptotic activities. </p>
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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>2 Selected Examples):</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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<h4>
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<span class="mim-font">
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<strong>.0001 AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IB</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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FASLG, 84-BP DEL, EX4
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<br />
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SNP: rs80358236,
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ClinVar: RCV000017959, RCV001789750
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<div>
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<span class="mim-text-font">
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<p>In a patient with SLE (152700) who exhibited lymphadenopathy, Wu et al. (1996) identified a heterozygous 84-bp deletion within exon 4 of the FASL gene, resulting in a predicted 28-amino acid in-frame deletion. </p><p>Lenardo (1999) suggested that this patient should be classified as having autoimmune lymphoproliferative syndrome (601859) due to mutation in the FASL gene. This form of ALPS has been designated ALPS1B, the form due to mutation in the FAS gene being ALPS1A.</p>
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</span>
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</div>
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<div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 LUNG CANCER, SUSCEPTIBILITY TO</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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FASLG, -844T-C
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<br />
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SNP: rs763110,
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gnomAD: rs763110,
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ClinVar: RCV000017960
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</span>
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<div>
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<span class="mim-text-font">
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<p>Zhang et al. (2005) genotyped 1,000 Han Chinese lung cancer (211980) patients and 1,270 controls for 2 functional polymorphisms in the promoter regions of the FAS and FASL genes, -1377G-A (134637.0021) and -844T-C, respectively. Compared to noncarriers, there was a 1.6-fold increased risk of developing lung cancer for carriers of the FAS -1377AA genotype and a 1.8-fold increased risk for carriers of the FASL -844CC genotype. Carriers of both homozygous genotypes had a more than 4-fold increased risk, indicative of multiplicative gene-gene interaction. </p>
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<div>
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<h4>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 11/16/2009<br>Paul J. Converse - updated : 8/20/2008<br>Patricia A. Hartz - updated : 3/4/2008<br>Patricia A. Hartz - updated : 2/7/2008<br>Paul J. Converse - updated : 6/19/2006<br>Cassandra L. Kniffin - updated : 6/2/2006<br>Paul J. Converse - updated : 11/8/2005<br>Marla J. F. O'Neill - updated : 7/21/2005<br>Paul J. Converse - updated : 8/11/2004<br>Paul J. Converse - updated : 4/19/2004<br>Cassandra L. Kniffin - updated : 3/12/2004<br>Paul J. Converse - updated : 5/29/2002<br>Ada Hamosh - updated : 4/9/2002<br>Paul J. Converse - updated : 2/25/2002<br>Paul J. Converse - updated : 10/4/2001<br>Victor A. McKusick - updated : 4/11/2001<br>Ada Hamosh - updated : 10/30/2000<br>Ada Hamosh - updated : 8/5/1999<br>Ada Hamosh - updated : 5/13/1999<br>Victor A. McKusick - updated : 2/3/1999<br>Ada Hamosh - updated : 10/15/1998<br>Victor A. McKusick - updated : 3/16/1997
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</span>
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</div>
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Victor A. McKusick : 4/12/1994
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carol : 02/27/2025<br>mgross : 11/11/2014<br>carol : 4/3/2013<br>carol : 2/6/2012<br>alopez : 11/20/2009<br>alopez : 11/18/2009<br>terry : 11/16/2009<br>terry : 11/16/2009<br>mgross : 8/28/2008<br>terry : 8/20/2008<br>mgross : 3/4/2008<br>mgross : 2/8/2008<br>mgross : 2/8/2008<br>terry : 2/7/2008<br>mgross : 6/19/2006<br>wwang : 6/2/2006<br>mgross : 11/8/2005<br>wwang : 10/27/2005<br>wwang : 7/25/2005<br>terry : 7/21/2005<br>carol : 11/17/2004<br>ckniffin : 11/2/2004<br>mgross : 8/11/2004<br>mgross : 8/11/2004<br>carol : 5/25/2004<br>mgross : 4/19/2004<br>alopez : 4/13/2004<br>alopez : 4/2/2004<br>ckniffin : 3/12/2004<br>mgross : 5/29/2002<br>cwells : 4/17/2002<br>cwells : 4/15/2002<br>cwells : 4/12/2002<br>terry : 4/9/2002<br>mgross : 2/25/2002<br>mgross : 2/25/2002<br>mcapotos : 10/4/2001<br>mgross : 10/4/2001<br>alopez : 5/10/2001<br>mcapotos : 4/18/2001<br>mcapotos : 4/12/2001<br>terry : 4/11/2001<br>mgross : 10/30/2000<br>alopez : 10/11/2000<br>alopez : 8/5/1999<br>alopez : 5/13/1999<br>terry : 5/13/1999<br>mgross : 5/10/1999<br>mgross : 5/10/1999<br>terry : 5/3/1999<br>carol : 2/8/1999<br>terry : 2/3/1999<br>alopez : 12/21/1998<br>alopez : 10/15/1998<br>terry : 5/29/1998<br>alopez : 3/16/1998<br>alopez : 3/16/1998<br>terry : 2/25/1998<br>terry : 2/25/1998<br>alopez : 7/29/1997<br>alopez : 7/7/1997<br>mark : 6/14/1997<br>mark : 3/16/1997<br>terry : 3/10/1997<br>mark : 2/23/1997<br>terry : 11/26/1996<br>mark : 10/17/1996<br>mark : 10/9/1996<br>mark : 12/13/1995<br>mark : 10/18/1995<br>warfield : 4/20/1994<br>carol : 4/12/1994
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