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Entry
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- *300386 - CD40 LIGAND; CD40LG
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- OMIM
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<div class="container hidden-print">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*300386</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#otherFeatures">Other Features</a>
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</li>
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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/300386">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000102245;t=ENST00000370629" 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=959" 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=300386" 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=ENSG00000102245;t=ENST00000370629" 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_000074" 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_000074" 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=300386" 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=02311&isoform_id=02311_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/CD40LG" 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/37270,38412,38484,180124,231718,1129042,1518170,4261682,4557433,33327534,37781608,47938257,49902362,51981909,71082685,114412926,117606558,119608868,119608869,119661246,119661257,158258711,226234692,229617461,313573559" 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/P29965" 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=959" 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=ENSG00000102245;t=ENST00000370629" 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=CD40LG" 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=CD40LG" 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+959" 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/CD40LG" 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:959" 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/959" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chrX&hgg_gene=ENST00000370629.7&hgg_start=136648158&hgg_end=136660390&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:11935" 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:11935" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/cd40lg" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=300386[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=300386[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/CD40LG/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000102245" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=CD40LG" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=CD40LG" 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=CD40LG" 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/CD40Lbase/" title="CD40Lbase: Mutation registry for X-linked Hyper-IgM syndrome" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">CD40Lbase: Mutation regist…</a></div><div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/CD40LG" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">CD40LG database at LOVD</a></div><div style="margin-left: 0.5em;"><a href="http://www.expasy.ch/cd40lbase/cd40lbasestruct.html" title="Immunodeficiency with Increased IgM-The European CD40 Defect Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Immunodeficiency with Incr…</a></div><div style="margin-left: 0.5em;"><a href="https://research.cchmc.org/LOVD2/home.php?select_db=CD40LG" 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=CD40LG&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/PA36626" 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:11935" 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:88337" 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/CD40LG#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:88337" 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/959/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=959" 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-100727-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:300386" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:959" 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=CD40LG&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 403835002<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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300386
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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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CD40 LIGAND; CD40LG
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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>
|
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<span class="mim-font">
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CD40 ANTIGEN LIGAND; CD40L<br />
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CD154<br />
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TNF-RELATED ACTIVATION PROTEIN; TRAP<br />
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TUMOR NECROSIS FACTOR LIGAND SUPERFAMILY, MEMBER 5; TNFSF5<br />
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GP39
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CD40LG" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CD40LG</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
|
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<strong>
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<em>
|
|
Cytogenetic location: <a href="/geneMap/X/724?start=-3&limit=10&highlight=724">Xq26.3</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:136648158-136660390&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">X:136,648,158-136,660,390</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>
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<div>
|
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<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>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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Phenotype
|
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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PheneGene Graphics <span class="caret"></span>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>The CD40LG gene encodes a transmembrane molecule, CD40 ligand, found on T cells.</p>
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<p><a href="#7" class="mim-tip-reference" title="Gauchat, J.-F., Aubry, J.-P., Mazzei, G., Life, P., Jomotte, T., Elson, G., Bonnefoy, J.-Y. <strong>Human CD40-ligand: molecular cloning, cellular distribution and regulation of expression by factors controlling IgE production.</strong> FEBS Lett. 315: 259-266, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7678552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7678552</a>] [<a href="https://doi.org/10.1016/0014-5793(93)81175-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7678552">Gauchat et al. (1993)</a> cloned the cDNA for human CD40 ligand (CD40LG) from a CD4-positive T-cell clone. The cDNA predicts a type II membrane protein of 261 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7678552" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#28" class="mim-tip-reference" title="Seyama, K., Kira, S., Ishidoh, K., Souma, S., Miyakawa, T., Kominami, E. <strong>Genomic structure and PCR-SSCP analysis of the human CD40 ligand gene: its application to prenatal screening for X-linked hyper-IgM syndrome.</strong> Hum. Genet. 97: 180-185, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8566950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8566950</a>] [<a href="https://doi.org/10.1007/BF02265262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8566950">Seyama et al. (1996)</a> reported that the CD40LG gene contains 5 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8566950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By virtue of the relation of CD40 ligand to the X-linked hyper-IgM syndrome (HIGM1; <a href="/entry/308230">308230</a>), the gene has been mapped to chromosome X. Padayachee et al. (<a href="#23" class="mim-tip-reference" title="Padayachee, M., Feighery, C., Finn, A., McKeown, C., Levinsky, R. J., Kinnon, C., Malcolm, S. <strong>Mapping of the X-linked form of hyper-IgM syndrome (HIGM1) to Xq26 by close linkage to HPRT.</strong> Genomics 14: 551-553, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1427881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1427881</a>] [<a href="https://doi.org/10.1016/s0888-7543(05)80270-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1427881">1992</a>, <a href="#24" class="mim-tip-reference" title="Padayachee, M., Levinsky, R. J., Kinnon, C., Finn, A., McKeown, C., Feighery, C., Notarangelo, L. D., Hendriks, R. W., Read, A. P., Malcolm, S. <strong>Mapping of the X linked form of hyper IgM syndrome (HIGM1).</strong> J. Med. Genet. 30: 202-205, 1993. Note: Erratum: J. Med. Genet. 30: 528 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8097258/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8097258</a>] [<a href="https://doi.org/10.1136/jmg.30.3.202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8097258">1993</a>) narrowed the location to Xq26 by multipoint linkage studies demonstrating that it is close to HPRT (<a href="/entry/308000">308000</a>), a gene that forms part of an extensive YAC contig mapping to Xq26; a maximum lod score of 4.89 was obtained. The existence of an easily scorable VNTR of 5 alleles within the HPRT gene means that other families with X-linked hyper-IgM syndrome are likely to be informative for this polymorphism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1427881+8097258" 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="#3" class="mim-tip-reference" title="Aruffo, A., Farrington, M., Hollenbaugh, D., Li, X., Milatovich, A., Nonoyama, S., Bajorath, J., Grosmaire, L. S., Stenkamp, R., Neubauer, M., Roberts, R. L., Noelle, R. J., Ledbetter, J. A., Francke, U., Ochs, H. D. <strong>The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome.</strong> Cell 72: 291-300, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7678782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7678782</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90668-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7678782">Aruffo et al. (1993)</a> mapped the GP39 gene to Xq26 by PCR analysis of a regional mapping panel, followed up by fluorescence in situ hybridization for precise localization. By YAC analysis, <a href="#26" class="mim-tip-reference" title="Pilia, G., Porta, B., Padayachee, M., Malcolm, S., Zucchi, I., Villa, A., Macchi, P., Vezzoni, P., Schlessinger, D. <strong>Human CD40L gene maps between DXS144E and DXS300 in Xq26.</strong> Genomics 22: 249-251, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7959785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7959785</a>] [<a href="https://doi.org/10.1006/geno.1994.1378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7959785">Pilia et al. (1994)</a> mapped the CD40L locus between DXS144E and DXS300 in Xq26 and determined its transcription to be from 5-prime centromeric to 3-prime telomeric. This corresponded to the site where the clinical phenotype of the hyper-IgM syndrome type 1 had been mapped. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7678782+7959785" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Allen, R. C., Armitage, R. J., Conley, M. E., Rosenblatt, H., Jenkins, N. A., Copeland, N. G., Bedell, M. A., Edelhoff, S., Disteche, C. M., Simoneaux, D. K., Fanslow, W. C., Belmont, J., Spriggs, M. K. <strong>CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome.</strong> Science 259: 990-993, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7679801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7679801</a>] [<a href="https://doi.org/10.1126/science.7679801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7679801">Allen et al. (1993)</a> mapped the CD40LG gene to the proximal region of the mouse X chromosome, linked to Hprt. Hprt maps to the Xq26-q27.2 region, which suggested that the human CD40LG gene would also map to this region. This was confirmed by fluorescence in situ hybridization studies of CD40LG by <a href="#8" class="mim-tip-reference" title="Graf, D., Korthauer, U., Mages, H. W., Senger, G., Kroczek, R. A. <strong>Cloning of TRAP, a ligand for CD40 on human T cells.</strong> Europ. J. Immun. 22: 3191-3194, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1280226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1280226</a>] [<a href="https://doi.org/10.1002/eji.1830221226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1280226">Graf et al. (1992)</a> and <a href="#1" class="mim-tip-reference" title="Allen, R. C., Armitage, R. J., Conley, M. E., Rosenblatt, H., Jenkins, N. A., Copeland, N. G., Bedell, M. A., Edelhoff, S., Disteche, C. M., Simoneaux, D. K., Fanslow, W. C., Belmont, J., Spriggs, M. K. <strong>CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome.</strong> Science 259: 990-993, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7679801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7679801</a>] [<a href="https://doi.org/10.1126/science.7679801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7679801">Allen et al. (1993)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7679801+1280226" 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 CD40 ligand molecule aids in stimulating B cells in the immune response. The CD40 molecule (<a href="/entry/109535">109535</a>) is a glycoprotein expressed on B lymphocytes, epithelial cells, and some carcinoma cells. Crosslinking of CD40 by anti-CD40 monoclonal antibodies mediates B cell proliferation, adhesion, and differentiation (<a href="#6" class="mim-tip-reference" title="DiSanto, J. P., Bonnefoy, J. Y., Gauchat, J. F., Fischer, A., de Saint Basile, G. <strong>CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM.</strong> Nature 361: 541-543, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8094231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8094231</a>] [<a href="https://doi.org/10.1038/361541a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8094231">DiSanto et al., 1993</a>; <a href="#11" class="mim-tip-reference" title="Hollenbaugh, D., Grosmaire, L. S., Kullas, C. D., Chalupny, N. J., Braesch-Andersen, S., Noelle, R. J., Stamenkovic, I., Ledbetter, J. A., Aruffo, A. <strong>The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity.</strong> EMBO J. 11: 4313-4321, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1385114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1385114</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1992.tb05530.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1385114">Hollenbaugh et al., 1992</a>). <a href="#7" class="mim-tip-reference" title="Gauchat, J.-F., Aubry, J.-P., Mazzei, G., Life, P., Jomotte, T., Elson, G., Bonnefoy, J.-Y. <strong>Human CD40-ligand: molecular cloning, cellular distribution and regulation of expression by factors controlling IgE production.</strong> FEBS Lett. 315: 259-266, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7678552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7678552</a>] [<a href="https://doi.org/10.1016/0014-5793(93)81175-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7678552">Gauchat et al. (1993)</a> demonstrated by Northern blot and FACS analysis that the human CD40 ligand can be detected on T cells but is absent from B cells and monocytes. It is expressed on both CD4- and CD8-positive T cells. They found that IL4 (<a href="/entry/147780">147780</a>), an inducer of IgE production, upregulated CD40LG mRNA levels while gamma-interferon (IFNG; <a href="/entry/147570">147570</a>), an inhibitor of IgE synthesis, reduced expression of CD40LG mRNA. Thus there appears to be a correlation between human CD40LG expression and IgE production. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1385114+8094231+7678552" 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>Since CD40 ligand is expressed on platelets and released from them on activation, <a href="#10" class="mim-tip-reference" title="Heeschen, C., Dimmeler, S., Hamm, C. W., van den Brand, M. J., Boersma, E., Zeiher, A. M., Simoons, M. L. <strong>Soluble CD40 ligand in acute coronary syndromes.</strong> New Eng. J. Med. 348: 1104-1111, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646667</a>] [<a href="https://doi.org/10.1056/NEJMoa022600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646667">Heeschen et al. (2003)</a> investigated its predictive value as a marker for clinical outcome and the therapeutic effect of inhibition of glycoprotein IIb (<a href="/entry/607759">607759</a>)/IIIa receptor (<a href="/entry/173470">173470</a>) in patients with acute coronary syndromes. Levels of soluble CD40 ligand were elevated in 221 patients with acute coronary syndromes (40.6%). Among patients receiving placebo, elevated soluble CD40 ligand levels indicated a significantly increased risk of death or nonfatal myocardial infarction during 6 months of follow-up. The prognostic value of this marker was validated in patients with chest pain, among whom elevated soluble CD40 ligand levels identified those with acute coronary syndromes who were at high risk for death or nonfatal myocardial infarction. This risk in these patients was reduced by treatment with abciximab, whereas there was no significant treatment effect of abciximab in patients with low levels of soluble CD40 ligand. <a href="#10" class="mim-tip-reference" title="Heeschen, C., Dimmeler, S., Hamm, C. W., van den Brand, M. J., Boersma, E., Zeiher, A. M., Simoons, M. L. <strong>Soluble CD40 ligand in acute coronary syndromes.</strong> New Eng. J. Med. 348: 1104-1111, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646667</a>] [<a href="https://doi.org/10.1056/NEJMoa022600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646667">Heeschen et al. (2003)</a> found that troponin T (<a href="/entry/191041">191041</a>) and soluble CD40 ligand have independent predictive value with respect to both the risk of ischemic events and the benefit of glycoprotein IIb/IIIa receptor inhibition by abciximab. They speculated that, whereas positivity for troponins may indicate the propensity of the thrombus to embolize, leading to myocardial necrosis, elevated soluble CD40 ligand levels in patients with acute coronary syndromes reflect the inflammatory thrombotic activity of the culprit lesion in recruiting and activating platelets. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12646667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a cohort of patients with acute coronary syndromes (195 cases, 195 controls), <a href="#34" class="mim-tip-reference" title="Varo, N., de Lemos, J. A., Libby, P., Morrow, D. A., Murphy, S. A., Nuzzo, R., Gibson, C. M., Cannon, C. P., Braunwald, E., Schonbeck, U. <strong>Soluble CD40L: risk prediction after acute coronary syndromes.</strong> Circulation 108: 1049-1052, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12912804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12912804</a>] [<a href="https://doi.org/10.1161/01.CIR.0000088521.04017.13" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12912804">Varo et al. (2003)</a> found that soluble CD40 ligand concentrations above the median were associated with risk for recurrent myocardial infarction or composite death/myocardial infarction within 10 months independent of other predictive variables, including troponin and C-reactive protein (CRP; <a href="/entry/123260">123260</a>). Congestive heart failure did not associate with soluble CD40 ligand. Patients with elevated plasma levels of soluble CD40 ligand and troponin showed a markedly increased risk of death or myocardial infarction compared with patients with the lowest levels of both markers (adjusted hazard ratios, 12.1 and 7.2, respectively; p less than 0.01 for both). <a href="#34" class="mim-tip-reference" title="Varo, N., de Lemos, J. A., Libby, P., Morrow, D. A., Murphy, S. A., Nuzzo, R., Gibson, C. M., Cannon, C. P., Braunwald, E., Schonbeck, U. <strong>Soluble CD40L: risk prediction after acute coronary syndromes.</strong> Circulation 108: 1049-1052, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12912804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12912804</a>] [<a href="https://doi.org/10.1161/01.CIR.0000088521.04017.13" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12912804">Varo et al. (2003)</a> stated that these findings support the hypothesis that CD40 ligand plays a central role in the pathophysiology of acute coronary syndromes and validate the report by <a href="#10" class="mim-tip-reference" title="Heeschen, C., Dimmeler, S., Hamm, C. W., van den Brand, M. J., Boersma, E., Zeiher, A. M., Simoons, M. L. <strong>Soluble CD40 ligand in acute coronary syndromes.</strong> New Eng. J. Med. 348: 1104-1111, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12646667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12646667</a>] [<a href="https://doi.org/10.1056/NEJMoa022600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12646667">Heeschen et al. (2003)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12912804+12646667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Cipollone, F., Ferri, C., Desideri, G., Paloscia, L., Materazzo, G., Mascellanti, M., Fazia, M., Iezzi, A., Cuccurullo, C., Pini, B., Bucci, M., Santucci, A., Cuccurullo, F., Mezzetti, A. <strong>Preprocedural level of soluble CD40L is predictive of enhanced inflammatory response and restenosis after coronary angioplasty.</strong> Circulation 108: 2776-2782, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14623801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14623801</a>] [<a href="https://doi.org/10.1161/01.CIR.0000103700.05109.0D" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14623801">Cipollone et al. (2003)</a> studied 70 patients who underwent percutaneous transluminal coronary angioplasty (PTCA) and had repeat angiograms at 6-month follow-up. They found that patients who developed post-PTCA restenosis had significantly increased levels of CD40L both before the procedure and as long as 6 months after PTCA. <a href="#5" class="mim-tip-reference" title="Cipollone, F., Ferri, C., Desideri, G., Paloscia, L., Materazzo, G., Mascellanti, M., Fazia, M., Iezzi, A., Cuccurullo, C., Pini, B., Bucci, M., Santucci, A., Cuccurullo, F., Mezzetti, A. <strong>Preprocedural level of soluble CD40L is predictive of enhanced inflammatory response and restenosis after coronary angioplasty.</strong> Circulation 108: 2776-2782, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14623801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14623801</a>] [<a href="https://doi.org/10.1161/01.CIR.0000103700.05109.0D" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14623801">Cipollone et al. (2003)</a> also identified preprocedural serum CD40L level as an independent predictor of late lumen loss after PTCA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14623801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 25 cigarette smokers and 25 nonsmokers, <a href="#9" class="mim-tip-reference" title="Harding, S. A., Sarma, J., Josephs, D. H., Cruden, N. L., Din, J. N., Twomey, P. J., Fox, K. A. A., Newby, D. E. <strong>Upregulation of the CD40/CD40 ligand dyad and platelet-monocyte aggregation in cigarette smokers.</strong> Circulation 109: 1926-1929, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15078798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15078798</a>] [<a href="https://doi.org/10.1161/01.CIR.0000127128.52679.E4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15078798">Harding et al. (2004)</a> found that smokers had increased concentrations of serum C-reactive protein, surface expression of CD40 on monocytes and of CD40L on platelets, and platelet-monocyte aggregates. The level of plasma cotinine, a nicotine metabolite, correlated with monocyte CD40 expression, platelet CD40L expression, and platelet-monocyte aggregates. <a href="#9" class="mim-tip-reference" title="Harding, S. A., Sarma, J., Josephs, D. H., Cruden, N. L., Din, J. N., Twomey, P. J., Fox, K. A. A., Newby, D. E. <strong>Upregulation of the CD40/CD40 ligand dyad and platelet-monocyte aggregation in cigarette smokers.</strong> Circulation 109: 1926-1929, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15078798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15078798</a>] [<a href="https://doi.org/10.1161/01.CIR.0000127128.52679.E4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15078798">Harding et al. (2004)</a> concluded that cigarette smokers have upregulation of the CD40/CD40L dyad and platelet-monocyte aggregation that might account for the atherothrombotic consequences of this major cardiovascular risk factor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15078798" 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>Epstein-Barr virus (EBV), which is implicated in numerous human diseases including lymphoid malignancies, persistently affects peripheral B cells and transforms them into lymphoblastoid cell lines. <a href="#12" class="mim-tip-reference" title="Imadome, K., Shirakata, M., Shimizu, N., Nonoyama, S., Yamanashi, Y. <strong>CD40 ligand is a critical effector of Epstein-Barr virus in host cell survival and transformation.</strong> Proc. Nat. Acad. Sci. 100: 7836-7840, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12805559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12805559</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12805559[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.1231363100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12805559">Imadome et al. (2003)</a> found that EBV equally infects B cells from patients with X-linked hyper-IgM syndrome (<a href="/entry/308230">308230</a>) and those from healthy donors; however, it hardly transformed X-linked hyper-IgM syndrome B cells because of the dysfunctional CD40L gene of the patients. Unlike CD40, CD40L is usually not expressed on B cells. However, <a href="#12" class="mim-tip-reference" title="Imadome, K., Shirakata, M., Shimizu, N., Nonoyama, S., Yamanashi, Y. <strong>CD40 ligand is a critical effector of Epstein-Barr virus in host cell survival and transformation.</strong> Proc. Nat. Acad. Sci. 100: 7836-7840, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12805559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12805559</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12805559[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.1231363100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12805559">Imadome et al. (2003)</a> found that EBV infection of normal B cells induced CD40L expression as a critical effector in host cell transformation and survival. Moreover, chronic active EBV infection of peripheral T cells, implicated in T cell malignancies, was associated with ectopic expression of CD40. These results suggested that EBV infection induces CD40L/CD40 signaling in host cells, which appears to play an essential role in its persistent infection and malignancies of lymphocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12805559" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Bossaller, L., Burger, J., Draeger, R., Grimbacher, B., Knoth, R., Plebani, A., Durandy, A., Baumann, U., Schlesier, M., Welcher, A. A., Peter, H. H., Warnatz, K. <strong>ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells.</strong> J. Immun. 177: 4927-4932, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16982935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16982935</a>] [<a href="https://doi.org/10.4049/jimmunol.177.7.4927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16982935">Bossaller et al. (2006)</a> found that CD40L-deficient patients, like ICOS (<a href="/entry/604558">604558</a>)-deficient patients, had abrogated germinal center formation and a severe reduction of CXCR5 (BLR1; <a href="/entry/601613">601613</a>)-positive T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16982935" 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="#33" class="mim-tip-reference" title="van Zelm, M. C., Bartol, S. J. W., Driessen, G. J., Mascart, F., Reisli, I., Franco, J. L., Wolska-Kusnierz, B., Kanegane, H., Boon, L., van Dongen, J. J. M., van der Burg, M. <strong>Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation.</strong> J. Allergy Clin. Immun. 134: 135-144, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24418477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24418477</a>] [<a href="https://doi.org/10.1016/j.jaci.2013.11.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24418477">van Zelm et al. (2014)</a> found reduced numbers of all memory B-cell subsets except CD27 (TNFRSF7; <a href="/entry/186711">186711</a>)-negative/IgA-positive B cells in both CD19 (<a href="/entry/107265">107265</a>)-deficient patients and CD40L-deficient patients compared with controls. Analysis of transcripts after class switching demonstrated that patient transcripts had fewer somatic mutations and reduced usage of IgG2 and IgA2 subclasses. There was also a deficiency in selection strength of mutations for antigen binding in patients compared with controls, whereas selection to maintain superantigen binding was normal. Selection against the autoreactive properties of immunoglobulins was impaired in patients. Somatic hypermutation analysis revealed decreased AICDA (<a href="/entry/605257">605257</a>) and UNG (<a href="/entry/191525">191525</a>) activity in CD40L deficiency, but increased UNG activity and decreased mismatch repair in CD19 deficiency. <a href="#33" class="mim-tip-reference" title="van Zelm, M. C., Bartol, S. J. W., Driessen, G. J., Mascart, F., Reisli, I., Franco, J. L., Wolska-Kusnierz, B., Kanegane, H., Boon, L., van Dongen, J. J. M., van der Burg, M. <strong>Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation.</strong> J. Allergy Clin. Immun. 134: 135-144, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24418477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24418477</a>] [<a href="https://doi.org/10.1016/j.jaci.2013.11.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24418477">Van Zelm et al. (2014)</a> concluded that both the B-cell antigen receptor and CD40 signaling pathways are required for selection of immunoglobulin reactivity, but that they differentially mediate DNA repair pathways during somatic hypermutation and thereby together shape the mature B-cell repertoire. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24418477" 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="#35" class="mim-tip-reference" title="Wang, J., Syrett, C. M., Kramer, M. C., Basu, A., Atchison, M. L., Anguera, M. C. <strong>Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X.</strong> Proc. Nat. Acad. Sci. 113: E2029-38, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27001848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27001848</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27001848[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.1520113113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27001848">Wang et al. (2016)</a> showed that chromatin of the inactive X chromosome (Xi) in female mouse and human mature naive T cells lacks the typical heterochromatic modifications of the Xi, resulting in partial reactivation of the Xi and leading to increased expression of immunity-related X-linked genes such as CD40LG and CXCR3 (<a href="/entry/300574">300574</a>). Analysis of B cells from female patients with systemic lupus erythematosus (SLE) revealed a different X chromosome silencing mechanism compared to controls, which likely caused partial reactivation of the Xi, thereby increasing biallelic expression of autoimmune-associated genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27001848" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 3 of 4 patients with hyper-IgM immunodeficiency syndrome type 1 (HIGM1; <a href="/entry/308230">308230</a>), <a href="#1" class="mim-tip-reference" title="Allen, R. C., Armitage, R. J., Conley, M. E., Rosenblatt, H., Jenkins, N. A., Copeland, N. G., Bedell, M. A., Edelhoff, S., Disteche, C. M., Simoneaux, D. K., Fanslow, W. C., Belmont, J., Spriggs, M. K. <strong>CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome.</strong> Science 259: 990-993, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7679801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7679801</a>] [<a href="https://doi.org/10.1126/science.7679801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7679801">Allen et al. (1993)</a> demonstrated point mutations in the CD40LG gene (<a href="#0003">300386.0003</a>-<a href="#0005">300386.0005</a>). Recombinant expression of 2 of the mutant CD40LG cDNAs resulted in proteins incapable of binding to CD40 and unable to induce proliferation or IgE secretion from normal B cells. Activated T cells from the 4 affected patients failed to express wildtype CD40LG, although their B cells responded normally to wildtype CD40LG. Patients with the hyper-IgM syndrome type 1 do not express IgE, strongly indicating that CD40LG is required (in conjunction with IL4) for production of IgE in vivo and suggests that it probably helps induce switching to all other isotypes. <a href="#14" class="mim-tip-reference" title="Korthauer, U., Graf, D., Mages, H. W., Briere, F., Padayachee, M., Malcolm, S., Ugazio, A. G., Notarangelo, L. D., Levinsky, R. J., Kroczek, R. A. <strong>Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM.</strong> Nature 361: 539-541, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7679206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7679206</a>] [<a href="https://doi.org/10.1038/361539a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7679206">Korthauer et al. (1993)</a> likewise followed up on the suggestion of a causal relationship of the condition they symbolized HIGM1 and the gene they symbolized TRAP (for TNF-related activation protein) and demonstrated to be the CD40 ligand. They presented evidence that point mutations in the TRAP gene give rise to nonfunctional or defective expression of TRAP on the surface of T cells in patients with this disorder. <a href="#6" class="mim-tip-reference" title="DiSanto, J. P., Bonnefoy, J. Y., Gauchat, J. F., Fischer, A., de Saint Basile, G. <strong>CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM.</strong> Nature 361: 541-543, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8094231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8094231</a>] [<a href="https://doi.org/10.1038/361541a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8094231">DiSanto et al. (1993)</a> found a lack of CD40LG in 4 unrelated boys with the hyper-IgM syndrome type 1. Furthermore, CD40LG transcripts in these patients showed either deletions or point mutations clustered within a limited region of the CD40LG extracellular domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8094231+7679206+7679801" 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="#3" class="mim-tip-reference" title="Aruffo, A., Farrington, M., Hollenbaugh, D., Li, X., Milatovich, A., Nonoyama, S., Bajorath, J., Grosmaire, L. S., Stenkamp, R., Neubauer, M., Roberts, R. L., Noelle, R. J., Ledbetter, J. A., Francke, U., Ochs, H. D. <strong>The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome.</strong> Cell 72: 291-300, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7678782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7678782</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90668-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7678782">Aruffo et al. (1993)</a> identified point mutations involving the extracellular domain of the gp39 protein in 2 patients with HIGM1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7678782" 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>See reviews by <a href="#16" class="mim-tip-reference" title="Kroczek, R. A., Graf, D., Brugnoni, D., Giliani, S., Korthauer, U., Ugazio, A., Senger, G., Mages, H. W., Villa, A., Notarangelo, L. D. <strong>Defective expression of CD40 ligand on T cell causes 'X-linked immunodeficiency with hyper-IgM (HIGM1)'.</strong> Immun. Rev. 138: 39-59, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7915248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7915248</a>] [<a href="https://doi.org/10.1111/j.1600-065x.1994.tb00846.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7915248">Kroczek et al. (1994)</a> and <a href="#27" class="mim-tip-reference" title="Ramesh, N., Fuleihan, R., Geha, R. <strong>Molecular pathology of X-linked immunoglobulin deficiency with normal or elevated IgM (HIGMX-1).</strong> Immun. Rev. 138: 87-104, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7520884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7520884</a>] [<a href="https://doi.org/10.1111/j.1600-065x.1994.tb00848.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7520884">Ramesh et al. (1994)</a>. <a href="#16" class="mim-tip-reference" title="Kroczek, R. A., Graf, D., Brugnoni, D., Giliani, S., Korthauer, U., Ugazio, A., Senger, G., Mages, H. W., Villa, A., Notarangelo, L. D. <strong>Defective expression of CD40 ligand on T cell causes 'X-linked immunodeficiency with hyper-IgM (HIGM1)'.</strong> Immun. Rev. 138: 39-59, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7915248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7915248</a>] [<a href="https://doi.org/10.1111/j.1600-065x.1994.tb00846.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7915248">Kroczek et al. (1994)</a> tabulated 17 mutations in the CD40L gene that had been identified as the cause of HIGM1. Three of these were different mutations in the same codon, trp140, resulting in a stop signal in 2 cases and in a nonconservative amino acid substitution, trp140-to-gly, in the other (<a href="#0008">300386.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7520884+7915248" 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="#19" class="mim-tip-reference" title="Macchi, P., Villa, A., Strina, D., Sacco, M. G., Morali, F., Brugnoni, D., Giliani, S., Mantuano, E., Fasth, A., Andersson, B., Zegers, B. J. M., Cavagni, G., Reznick, I., Levy, J., Zan-Bar, I., Porat, Y., Airo, P., Plebani, A., Vezzoni, P., Notarangelo, L. D. <strong>Characterization of nine novel mutations in the CD40 ligand gene in patients with X-linked hyper IgM syndrome of various ancestry.</strong> Am. J. Hum. Genet. 56: 898-906, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7717401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7717401</a>]" pmid="7717401">Macchi et al. (1995)</a> characterized 9 novel mutations in the CD40LG gene in patients with X-linked hyper-IgM syndrome of various ancestry. They found 2 nonsense mutations, 3 missense mutations, 1 4-bp deletion, and 3 small insertions. One of the nonsense mutations involved a change of codon 140 from TGG to TGA (trp140-to-ter). Trp140-to-ter resulting from a TGG-to-TAG mutation was previously reported (<a href="#0007">300386.0007</a>). One of the missense mutations involved a change of codon 140 from TGG (trp) to CGG (arg); previously reported was a mutation in codon 140 changing it from TGG (trp) to GGG (gly) (<a href="#0008">300386.0008</a>). Thus, 4 different point mutations had been observed in codon 140 in patients with the hyper-IgM syndrome type 1, suggesting that it may be a hotspot for mutation. <a href="#21" class="mim-tip-reference" title="Nonoyama, S., Shimadzu, M., Toru, H., Seyama, K., Nunoi, H., Neubauer, M., Yata, J., Och, H. D. <strong>Mutations of the CD40 ligand gene in 13 Japanese patients with X-linked hyper-IgM syndrome.</strong> Hum. Genet. 99: 624-627, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150729</a>] [<a href="https://doi.org/10.1007/s004390050417" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9150729">Nonoyama et al. (1997)</a> reported mutations in the CD40 ligand gene in 13 Japanese patients. Nine mutations were novel and included missense, nonsense, splice site, and genomic deletion mutations. Two of the mutations were at trp140, further confirming that codon as a mutation hotspot. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7717401+9150729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Lin, Q., Rohrer, J., Allen, R. C., Larche, M., Greene, J. M., Shigeoka, A. O., Gatti, R. A., Derauf, D. C., Belmont, J. W., Conley, M. E. <strong>A single strand conformation polymorphism study of CD40 ligand: efficient mutation analysis and carrier detection of X-linked hyper IgM syndrome.</strong> J. Clin. Invest. 97: 196-201, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8550833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8550833</a>] [<a href="https://doi.org/10.1172/JCI118389" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8550833">Lin et al. (1996)</a> succeeded in finding 11 different mutations in all 13 patients whose activated T cells failed to bind a recombinant CD40 construct. The exact nature of 4 of these mutations, a deletion and 3 splice defects, could not be determined by cDNA sequencing. In addition, SSCP analysis permitted rapid carrier detection in 2 families in whom the source of the mutation was most likely a male with gonadal mosaicism who passed the disorder on to some, but not all, of his daughters. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8550833" 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 SSCP analysis in the study of the CD40LG gene in affected boys from 19 unrelated families, <a href="#13" class="mim-tip-reference" title="Katz, F., Hinshelwood, S., Rutland, P., Jones, A., Kinnon, C., Morgan, G. <strong>Mutation analysis in CD40 ligand deficiency leading to X-linked hypogammaglobulinemia with hyper IgM syndrome.</strong> Hum. Mutat. 8: 223-228, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8889581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8889581</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1996)8:3<223::AID-HUMU5>3.0.CO;2-A" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8889581">Katz et al. (1996)</a> identified 16 novel mutations: 6 patients had single base substitutions, 2 patients had single base insertions, 6 patients had deletions ranging from 1 to 7 bases, and 2 patients had large deletions at the 5-prime end of the gene. The mutations were distributed throughout the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8889581" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 30 families, <a href="#29" class="mim-tip-reference" title="Seyama, K., Nonoyama, S., Gangsaas, I., Hollenbaugh, D., Pabst, H. F., Aruffo, A., Ochs, H. D. <strong>Mutations of the CD40 ligand gene and its effect on CD40 ligand expression in patients with X-linked hyper IgM syndrome.</strong> Blood 92: 2421-2434, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9746782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9746782</a>]" pmid="9746782">Seyama et al. (1998)</a> identified 28 unique mutations of the CD40LG gene, including 9 missense, 5 nonsense, 9 splice site, and 5 deletion/insertion mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9746782" 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>After screening the entire CD40L gene and identifying 22 single-nucleotide polymorphisms (SNPs), <a href="#22" class="mim-tip-reference" title="Onouchi, Y., Onoue, S., Tamari, M., Wakui, K., Fukushima, Y., Yashiro, M., Nakamura, Y., Yanagawa, H., Kishi, F., Ouchi, K., Terai, M., Hamamoto, K., and 10 others. <strong>CD40 ligand gene and Kawasaki disease.</strong> Europ. J. Hum. Genet. 12: 1062-1068, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15367912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15367912</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15367912">Onouchi et al. (2004)</a> performed an association study with 427 Japanese Kawasaki disease patients and 476 healthy Japanese controls. A SNP in intron 4 (IVS4+121A-G) that was marginally overrepresented in Kawasaki patients was found to be significantly more frequent in male Kawasaki disease patients with coronary artery lesions compared to controls (OR, 2.0; 95% CI, 1.07-3.66; p = 0.030). This SNP was extremely rare in a control Caucasian population (0.7%). <a href="#22" class="mim-tip-reference" title="Onouchi, Y., Onoue, S., Tamari, M., Wakui, K., Fukushima, Y., Yashiro, M., Nakamura, Y., Yanagawa, H., Kishi, F., Ouchi, K., Terai, M., Hamamoto, K., and 10 others. <strong>CD40 ligand gene and Kawasaki disease.</strong> Europ. J. Hum. Genet. 12: 1062-1068, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15367912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15367912</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15367912">Onouchi et al. (2004)</a> suggested that CD40L has a role in the pathogenesis of coronary artery lesions and that this might explain the excess of males affected with Kawasaki disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15367912" 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="Palterer, B., Salvati, L., Capone, M., Mecheri, V., Maggi, L., Mazzoni, A., Cosmi, L., Volpi, N., Tiberi, L., Provenzano, A., Giglio, S., Parronchi, P., Maggiore, G., Gallo, O., Bartoloni, A., Annunziato, F., Zammarchi, L., Liotta, F. <strong>Variant disrupting CD40L transmembrane domain and atypical X-linked hyper-IgM syndrome: a case report with leishmaniasis and review of the literature.</strong> Front. Immun. 13: 840767, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35572607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35572607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35572607[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/10.3389/fimmu.2022.840767" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35572607">Palterer et al. (2022)</a> identified a heterozygous missense mutation (M36K; <a href="#0015">300386.0015</a>) in the transmembrane domain of the CD40LG gene in a 41-year-old man with HIGM1. The expression of CD40L was reduced on activated T CD4+ cells from the patient. The patient had an atypical clinical presentation that included leishmaniasis and hypogammaglobulinemia. <a href="#25" class="mim-tip-reference" title="Palterer, B., Salvati, L., Capone, M., Mecheri, V., Maggi, L., Mazzoni, A., Cosmi, L., Volpi, N., Tiberi, L., Provenzano, A., Giglio, S., Parronchi, P., Maggiore, G., Gallo, O., Bartoloni, A., Annunziato, F., Zammarchi, L., Liotta, F. <strong>Variant disrupting CD40L transmembrane domain and atypical X-linked hyper-IgM syndrome: a case report with leishmaniasis and review of the literature.</strong> Front. Immun. 13: 840767, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35572607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35572607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35572607[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/10.3389/fimmu.2022.840767" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35572607">Palterer et al. (2022)</a> concluded that variants in the transmembrane domain of CD40LG act as hypomorphic variants and could lead to atypical clinical features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35572607" 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>Alzheimer disease (<a href="/entry/104300">104300</a>) has a substantial inflammatory component, and activated microglia may play a central role in neuronal degeneration. <a href="#32" class="mim-tip-reference" title="Tan, J., Town, T., Paris, D., Mori, T., Suo, Z., Crawford, F., Mattson, M. P., Flavell, R. A., Mullan, M. <strong>Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation.</strong> Science 286: 2352-2355, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10600748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10600748</a>] [<a href="https://doi.org/10.1126/science.286.5448.2352" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10600748">Tan et al. (1999)</a> demonstrated that CD40 expression was increased on cultured microglia treated with freshly solubilized amyloid-beta (<a href="/entry/104760">104760</a>) and on microglia from a transgenic murine model of Alzheimer disease (Tg APPsw). Increased TNF-alpha (<a href="/entry/191160">191160</a>) production and induction of neuronal injury occurred when amyloid-beta-stimulated microglia were treated with CD40 ligand. Microglia from Tg APPsw mice deficient for CD40 ligand had less activation, suggesting that the CD40-CD40 ligand interaction is necessary for amyloid-beta-induced microglial activation. In addition, abnormal tau (<a href="/entry/157140">157140</a>) phosphorylation was reduced in Tg APPsw animals deficient for CD40 ligand, suggesting that the CD40-CD40 ligand interaction is an early event in Alzheimer disease pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10600748" 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 transgenic mice overproducing beta-amyloid but deficient in CD40L, <a href="#31" class="mim-tip-reference" title="Tan, J., Town, T., Crawford, F., Mori, T., DelleDonne, A., Crescentini, R., Obregon, D., Flavell, R. A., Mullan, M. J. <strong>Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice.</strong> Nature Neurosci. 5: 1288-1293, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12402041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12402041</a>] [<a href="https://doi.org/10.1038/nn968" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12402041">Tan et al. (2002)</a> found decreased astrocytosis and microgliosis associated with diminished beta-amyloid levels and decreased beta-amyloid plaque load. In mice with functional CD40L, anti-CD40L antibody similarly caused marked attenuation of beta-amyloid pathology. In both groups of mice, there was a shift from amyloidogenic to nonamyloidogenic APP processing, suggesting a mechanism by which reduction of available CD40L decreases beta-amyloid pathology. Further evidence suggested an increase in brain-to-blood clearance of beta-amyloid. These results supported a role for the CD40-CD40L interaction in the pathogenesis of amyloid pathology in AD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12402041" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Straw, A. D., MacDonald, A. S., Denkers, E. Y., Pearce, E. J. <strong>CD154 plays a central role in regulating dendritic cell activation during infections that induce Th1 or Th2 responses.</strong> J. Immun. 170: 727-734, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12517934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12517934</a>] [<a href="https://doi.org/10.4049/jimmunol.170.2.727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12517934">Straw et al. (2003)</a> found that activation of dendritic cells, which was observed during infection of wildtype mice with either the Th2-inducing parasite Schistosoma mansoni or the Th1-inducing parasite Toxoplasma gondii, did not occur in Cd154 -/- mice. The results indicated a major role for CD40-CD154 interaction in maintaining dendritic cell activation during infection, regardless of whether the outcome is a Th1 or a Th2 response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12517934" 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="#20" class="mim-tip-reference" title="McGregor, C. M., Schoenberger, S. P., Green, E. A. <strong>CD154 is a negative regulator of autoaggressive CD8(+) T cells in type 1 diabetes.</strong> Proc. Nat. Acad. Sci. 101: 9345-9350, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15192149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15192149</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15192149[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.0402807101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15192149">McGregor et al. (2004)</a> investigated the role of Cd154 in regulating anti-islet CD8 (see <a href="/entry/186910">186910</a>)-positive T cells in a mouse model of type I diabetes (<a href="/entry/222100">222100</a>), which was generated by islet-specific expression of Tnfa and Cd80 (<a href="/entry/112203">112203</a>). Their findings indicated that signaling through CD40-CD154 is critical in regulating autoaggressive CD8-positive T cells. This pathway was required to increase regulatory T-cell number and to sensitize autoaggressive T cells to suppression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15192149" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using unbiased transcript profiling in a mouse model of amyotrophic lateral sclerosis (ALS; see <a href="/entry/105400">105400</a>), <a href="#18" class="mim-tip-reference" title="Lincecum, J. M., Vieira, F. G., Wang, M. Z., Thompson, K., De Zutter, G. S., Kidd, J., Moreno, A., Sanchez, R., Carrion, I. J., Levine, B. A., Al-Nakhala, B. M., Sullivan, S. M., Gill, A., Perrin, S. <strong>From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis.</strong> Nature Genet. 42: 392-399, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20348957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20348957</a>] [<a href="https://doi.org/10.1038/ng.557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20348957">Lincecum et al. (2010)</a> identified a role for the costimulatory pathway, a key regulator of immune responses. <a href="#18" class="mim-tip-reference" title="Lincecum, J. M., Vieira, F. G., Wang, M. Z., Thompson, K., De Zutter, G. S., Kidd, J., Moreno, A., Sanchez, R., Carrion, I. J., Levine, B. A., Al-Nakhala, B. M., Sullivan, S. M., Gill, A., Perrin, S. <strong>From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis.</strong> Nature Genet. 42: 392-399, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20348957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20348957</a>] [<a href="https://doi.org/10.1038/ng.557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20348957">Lincecum et al. (2010)</a> observed that this pathway is upregulated in the blood of 56% of human patients with ALS. A therapy using a monoclonal antibody to CD40L was developed that slowed weight loss, delayed paralysis, and extended survival in an ALS mouse model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20348957" 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>15 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=300386[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 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
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CD40LG, ALA235PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894771 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894771;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=rs104894771" 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=rs104894771" 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=RCV000011907" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011907" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011907</a>
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<p>In a patient with hyper-IgM syndrome-1 (HIGM1; <a href="/entry/308230">308230</a>), <a href="#3" class="mim-tip-reference" title="Aruffo, A., Farrington, M., Hollenbaugh, D., Li, X., Milatovich, A., Nonoyama, S., Bajorath, J., Grosmaire, L. S., Stenkamp, R., Neubauer, M., Roberts, R. L., Noelle, R. J., Ledbetter, J. A., Francke, U., Ochs, H. D. <strong>The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome.</strong> Cell 72: 291-300, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7678782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7678782</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90668-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7678782">Aruffo et al. (1993)</a> identified a G-to-C transversion at position 724 (numbering according to <a href="#11" class="mim-tip-reference" title="Hollenbaugh, D., Grosmaire, L. S., Kullas, C. D., Chalupny, N. J., Braesch-Andersen, S., Noelle, R. J., Stamenkovic, I., Ledbetter, J. A., Aruffo, A. <strong>The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity.</strong> EMBO J. 11: 4313-4321, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1385114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1385114</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1992.tb05530.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1385114">Hollenbaugh et al., 1992</a>) predicted to result in replacement of ala235 by pro in the cDNA encoding CD40 ligand. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1385114+7678782" 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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CD40LG, SER128ARG AND GLU129GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894772 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894772;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=rs104894772" 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=rs104894772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894773 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894773;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=rs104894773" 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=rs104894773" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011908" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011908" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011908</a>
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<p>In a patient with hype-IgM syndrome-1 (HIGM1; <a href="/entry/308230">308230</a>), <a href="#3" class="mim-tip-reference" title="Aruffo, A., Farrington, M., Hollenbaugh, D., Li, X., Milatovich, A., Nonoyama, S., Bajorath, J., Grosmaire, L. S., Stenkamp, R., Neubauer, M., Roberts, R. L., Noelle, R. J., Ledbetter, J. A., Francke, U., Ochs, H. D. <strong>The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome.</strong> Cell 72: 291-300, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7678782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7678782</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90668-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7678782">Aruffo et al. (1993)</a> identified 3 nucleotide changes, a silent change of T to C at position 169, a T to A substitution at position 405, and an A to G substitution at position 407 in the cDNA encoding CD40 ligand. The last 2 changes resulted in the replacement of serine-128 by arginine and glutamic acid-129 by glycine, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7678782" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
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CD40LG, GLY227VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894768 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894768;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=rs104894768" 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=rs104894768" 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=RCV000011909" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011909" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011909</a>
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<p><a href="#1" class="mim-tip-reference" title="Allen, R. C., Armitage, R. J., Conley, M. E., Rosenblatt, H., Jenkins, N. A., Copeland, N. G., Bedell, M. A., Edelhoff, S., Disteche, C. M., Simoneaux, D. K., Fanslow, W. C., Belmont, J., Spriggs, M. K. <strong>CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome.</strong> Science 259: 990-993, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7679801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7679801</a>] [<a href="https://doi.org/10.1126/science.7679801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7679801">Allen et al. (1993)</a> identified a substitution of valine for glycine at position 227 of the CD40LG gene in a patient with hyper-IgM syndrome-1 (HIGM1; <a href="/entry/308230">308230</a>) (the codons were numbered from the initiating methionine). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7679801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894769 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894769;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=rs104894769" 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=rs104894769" 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=RCV000011910 OR RCV001507548" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011910, RCV001507548" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011910...</a>
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<p><a href="#1" class="mim-tip-reference" title="Allen, R. C., Armitage, R. J., Conley, M. E., Rosenblatt, H., Jenkins, N. A., Copeland, N. G., Bedell, M. A., Edelhoff, S., Disteche, C. M., Simoneaux, D. K., Fanslow, W. C., Belmont, J., Spriggs, M. K. <strong>CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome.</strong> Science 259: 990-993, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7679801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7679801</a>] [<a href="https://doi.org/10.1126/science.7679801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7679801">Allen et al. (1993)</a> identified a substitution of proline for leucine at position 155 of the CD40LG gene in a patient with hyper-IgM syndrome type 1 (HIGM1; <a href="/entry/308230">308230</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7679801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
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CD40LG, THR211ASP
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011911" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011911" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011911</a>
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<p><a href="#1" class="mim-tip-reference" title="Allen, R. C., Armitage, R. J., Conley, M. E., Rosenblatt, H., Jenkins, N. A., Copeland, N. G., Bedell, M. A., Edelhoff, S., Disteche, C. M., Simoneaux, D. K., Fanslow, W. C., Belmont, J., Spriggs, M. K. <strong>CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome.</strong> Science 259: 990-993, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7679801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7679801</a>] [<a href="https://doi.org/10.1126/science.7679801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7679801">Allen et al. (1993)</a> identified a substitution of aspartic acid for threonine at position 211 of the CD40LG gene in a patient with hyper-IgM syndrome-1 (HIGM1; <a href="/entry/308230">308230</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7679801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
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CD40LG, MET36ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894774 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894774;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=rs104894774" 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=rs104894774" 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=RCV000011912" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011912" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011912</a>
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<p>In a boy with hyper-IgM syndrome-1 (HIGM1; <a href="/entry/308230">308230</a>), <a href="#14" class="mim-tip-reference" title="Korthauer, U., Graf, D., Mages, H. W., Briere, F., Padayachee, M., Malcolm, S., Ugazio, A. G., Notarangelo, L. D., Levinsky, R. J., Kroczek, R. A. <strong>Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM.</strong> Nature 361: 539-541, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7679206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7679206</a>] [<a href="https://doi.org/10.1038/361539a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7679206">Korthauer et al. (1993)</a> described a T-to-G transversion of nucleotide 163 converting codon 36 from ATG (met) to AGG (arg). The mutation was located in the part of the gene encoding the transmembrane portion of the CD40 ligand. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7679206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0007" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0007 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
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CD40LG, TRP140TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894775 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894775;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=rs104894775" 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=rs104894775" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894776 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894776;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=rs104894776" 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=rs104894776" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011913" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011913" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011913</a>
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<p>In a boy with hyper-IgM syndrome-1 (HIGM1; <a href="/entry/308230">308230</a>), <a href="#14" class="mim-tip-reference" title="Korthauer, U., Graf, D., Mages, H. W., Briere, F., Padayachee, M., Malcolm, S., Ugazio, A. G., Notarangelo, L. D., Levinsky, R. J., Kroczek, R. A. <strong>Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM.</strong> Nature 361: 539-541, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7679206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7679206</a>] [<a href="https://doi.org/10.1038/361539a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7679206">Korthauer et al. (1993)</a> identified an amber nonsense mutation: a G-to-A transition of nucleotide 475 changed codon 140 from TGG (trp) to TAG (stop). See also <a href="#19" class="mim-tip-reference" title="Macchi, P., Villa, A., Strina, D., Sacco, M. G., Morali, F., Brugnoni, D., Giliani, S., Mantuano, E., Fasth, A., Andersson, B., Zegers, B. J. M., Cavagni, G., Reznick, I., Levy, J., Zan-Bar, I., Porat, Y., Airo, P., Plebani, A., Vezzoni, P., Notarangelo, L. D. <strong>Characterization of nine novel mutations in the CD40 ligand gene in patients with X-linked hyper IgM syndrome of various ancestry.</strong> Am. J. Hum. Genet. 56: 898-906, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7717401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7717401</a>]" pmid="7717401">Macchi et al. (1995)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7679206+7717401" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
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CD40LG, TRP140GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894777 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894777;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=rs104894777" 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=rs104894777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011914 OR RCV000256172" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011914, RCV000256172" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011914...</a>
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<p>In a boy with hyper-IgM syndrome-1 (HIGM1; <a href="/entry/308230">308230</a>), <a href="#14" class="mim-tip-reference" title="Korthauer, U., Graf, D., Mages, H. W., Briere, F., Padayachee, M., Malcolm, S., Ugazio, A. G., Notarangelo, L. D., Levinsky, R. J., Kroczek, R. A. <strong>Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM.</strong> Nature 361: 539-541, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7679206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7679206</a>] [<a href="https://doi.org/10.1038/361539a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7679206">Korthauer et al. (1993)</a> identified a T-to-G transversion of nucleotide 474 which converted codon 140 from TGG (trp) to GGG (gly). The mutation was located in the part of the gene encoding the extracellular part of the CD40 ligand. See also <a href="#19" class="mim-tip-reference" title="Macchi, P., Villa, A., Strina, D., Sacco, M. G., Morali, F., Brugnoni, D., Giliani, S., Mantuano, E., Fasth, A., Andersson, B., Zegers, B. J. M., Cavagni, G., Reznick, I., Levy, J., Zan-Bar, I., Porat, Y., Airo, P., Plebani, A., Vezzoni, P., Notarangelo, L. D. <strong>Characterization of nine novel mutations in the CD40 ligand gene in patients with X-linked hyper IgM syndrome of various ancestry.</strong> Am. J. Hum. Genet. 56: 898-906, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7717401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7717401</a>]" pmid="7717401">Macchi et al. (1995)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7679206+7717401" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
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</span>
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CD40LG, 63-BP DEL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2148552900 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2148552900;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=rs2148552900" 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=rs2148552900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011915" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011915" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011915</a>
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<p>In a boy with hyper-IgM syndrome-1 (HIGM1; <a href="/entry/308230">308230</a>), <a href="#6" class="mim-tip-reference" title="DiSanto, J. P., Bonnefoy, J. Y., Gauchat, J. F., Fischer, A., de Saint Basile, G. <strong>CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM.</strong> Nature 361: 541-543, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8094231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8094231</a>] [<a href="https://doi.org/10.1038/361541a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8094231">DiSanto et al. (1993)</a> identified a 63-bp (bases 385-447) deletion, removing the 21 amino acid residues from position 116 to 136 of the CD40LG protein. Two other patients showed small deletions (of 8 bp, <a href="#0010">300386.0010</a> and 10 bp, <a href="#0011">300386.0011</a>) in precisely the same region of the CD40LG molecule (bases 447-457). <a href="#6" class="mim-tip-reference" title="DiSanto, J. P., Bonnefoy, J. Y., Gauchat, J. F., Fischer, A., de Saint Basile, G. <strong>CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM.</strong> Nature 361: 541-543, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8094231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8094231</a>] [<a href="https://doi.org/10.1038/361541a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8094231">DiSanto et al. (1993)</a> hypothesized that the latter 2 patients may have possessed splice site mutations, as the deletions in these cases represented cryptic donor sites. The predicted mutant proteins would be truncated in these 2 cases, 138 amino acids in one, and 144 amino acids in the second, owing to a frameshift, with the introduction of premature stop codons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8094231" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011916" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011916" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011916</a>
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<p>In a patient (P2) with hyper-IgM syndrome-1 (HIGM1; <a href="/entry/308230">308230</a>), <a href="#6" class="mim-tip-reference" title="DiSanto, J. P., Bonnefoy, J. Y., Gauchat, J. F., Fischer, A., de Saint Basile, G. <strong>CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM.</strong> Nature 361: 541-543, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8094231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8094231</a>] [<a href="https://doi.org/10.1038/361541a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8094231">DiSanto et al. (1993)</a> identified a 8-bp deletion in the CD40LG gene. Also see <a href="/entry/308230#0009">308230.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8094231" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011917" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011917" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011917</a>
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<p>In a patient (P4) with hyper-IgM syndrome syndrome-1 (HIGM1; <a href="/entry/308230">308230</a>), <a href="#6" class="mim-tip-reference" title="DiSanto, J. P., Bonnefoy, J. Y., Gauchat, J. F., Fischer, A., de Saint Basile, G. <strong>CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM.</strong> Nature 361: 541-543, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8094231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8094231</a>] [<a href="https://doi.org/10.1038/361541a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8094231">DiSanto et al. (1993)</a> identified a 10-bp deletion in the CD40LG gene. Also see <a href="/entry/308230#0009">308230.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8094231" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104894778 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894778;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/rs104894778?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=rs104894778" 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=rs104894778" 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=RCV000011918" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011918" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011918</a>
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<p>In a patient with hyper-IgM syndrome-1 (HIGM1; <a href="/entry/308230">308230</a>), <a href="#6" class="mim-tip-reference" title="DiSanto, J. P., Bonnefoy, J. Y., Gauchat, J. F., Fischer, A., de Saint Basile, G. <strong>CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM.</strong> Nature 361: 541-543, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8094231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8094231</a>] [<a href="https://doi.org/10.1038/361541a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8094231">DiSanto et al. (1993)</a> demonstrated a C-to-A transversion at base 407 in a CpG dinucleotide, resulting in change of codon 123 from GCG (ala) to GAG (glu). The same mutation was found in heterozygous state in the mother. The mother was also informative for a polymorphic microsatellite repeat present in the 3-prime untranslated region of the CD40LG gene, thus allowing for the identification of normal and affected CD40LG alleles. Segregation of this CA repeat in sorted CD40LG(+) and CD40LG(-) cell populations in the mother revealed the normal allele in the CD40LG(+) population, whereas the CD40LG(-) population carried the mutant allele. This result indicated that the ala123-to-glu substitution results in a CD40LG molecule that is unable to bind CD40. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8094231" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
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CD40LG, 1-BP INS, TTT-TTTT, FS84TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs193922134 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs193922134;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=rs193922134" 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=rs193922134" 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=RCV000011919" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011919" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011919</a>
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<p>Hyper-IgM syndrome-1 (HIGM1; <a href="/entry/308230">308230</a>) was diagnosed on the basis of serum immunoglobulin levels in a 13-year-old boy with sclerosing cholangitis who had received a liver transplant (<a href="#15" class="mim-tip-reference" title="Kraakman, M. E. M., de Weers, M., Espanol, T., Schuurman, R. K. B., Hendriks, R. W. <strong>Identification of a CD40L gene mutation and genetic counselling in a family with immunodeficiency with hyperimmunoglobulinemia M.</strong> Clin. Genet. 48: 46-48, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7586644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7586644</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1995.tb04053.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7586644">Kraakman et al., 1995</a>). His brother died at 7 months of age from Pneumocystis carinii pneumonia. <a href="#15" class="mim-tip-reference" title="Kraakman, M. E. M., de Weers, M., Espanol, T., Schuurman, R. K. B., Hendriks, R. W. <strong>Identification of a CD40L gene mutation and genetic counselling in a family with immunodeficiency with hyperimmunoglobulinemia M.</strong> Clin. Genet. 48: 46-48, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7586644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7586644</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1995.tb04053.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7586644">Kraakman et al. (1995)</a> demonstrated that the patient had an insertional mutation of an extra T and a run of 4 T's at position 231-234 in the second exon of their cDNA, leading to a frameshift and a premature stop at nucleotide position 297. After translation, a truncated protein would result, containing the first 63 of the 261 CD40L amino acids, followed by 21 unrelated amino acids. The run of T's was flanked by an internally palindromic direct repeat sequence (TTACATGAA) at nucleotide positions 221 and 238, the presence of which may have facilitated the T insertion at position 231. Satisfactory genetic counseling was possible because testing demonstrated that, whereas the patient's mother was a carrier, his clinically normal sister was not a carrier. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7586644" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011920" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011920" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011920</a>
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<p>In a male infant with hyper-IgM syndrome-1 (HIGM1; <a href="/entry/308230">308230</a>), <a href="#2" class="mim-tip-reference" title="Apoil, P. A., Kuhlein, E., Robert, A., Rubie, H., Blancher, A. <strong>HIGM syndrome caused by insertion of an AluYb8 element in exon 1 of the CD40LG gene.</strong> Immunogenetics 59: 17-23, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17146684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17146684</a>] [<a href="https://doi.org/10.1007/s00251-006-0175-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17146684">Apoil et al. (2007)</a> identified an inactivating mutation in the CD40LG gene resulting from insertion of an AluYb8 element in exon 1. Flow cytometry showed that the mutation led to total deficiency of CD40LG expression in T lymphocytes. The patient's parents and female sib had normal Ig levels. Only 30% of the mother's stimulated T cells expressed CD40LG, compared with 60 to 70% in controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17146684" 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>.0015 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894774 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894774;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=rs104894774" 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=rs104894774" 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=RCV000480912 OR RCV001368065" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000480912, RCV001368065" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000480912...</a>
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<p>In a 41-year-old man with hyper-IgM syndrome-1 (HIGM1; <a href="/entry/308230">308230</a>), <a href="#25" class="mim-tip-reference" title="Palterer, B., Salvati, L., Capone, M., Mecheri, V., Maggi, L., Mazzoni, A., Cosmi, L., Volpi, N., Tiberi, L., Provenzano, A., Giglio, S., Parronchi, P., Maggiore, G., Gallo, O., Bartoloni, A., Annunziato, F., Zammarchi, L., Liotta, F. <strong>Variant disrupting CD40L transmembrane domain and atypical X-linked hyper-IgM syndrome: a case report with leishmaniasis and review of the literature.</strong> Front. Immun. 13: 840767, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35572607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35572607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35572607[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/10.3389/fimmu.2022.840767" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35572607">Palterer et al. (2022)</a> identified a heterozygous c.107T-A transversion in the CD40LG gene, resulting in a met36-to-lys (M36K) substitution in the transmembrane domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was absent in the gnomAD and 1000 Genomes Project databases. The expression of CD40L was reduced on activated T CD4+ cells from the patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35572607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1007/s00251-006-0175-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.4049/jimmunol.177.7.4927" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.CIR.0000103700.05109.0D" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1996)8:3<223::AID-HUMU5>3.0.CO;2-A" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.30.3.202" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.3389/fimmu.2022.840767" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12517934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12517934</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12517934" 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.170.2.727" 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="31" class="mim-anchor"></a>
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<a id="Tan2002" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Tan, J., Town, T., Crawford, F., Mori, T., DelleDonne, A., Crescentini, R., Obregon, D., Flavell, R. A., Mullan, M. J.
|
|
<strong>Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice.</strong>
|
|
Nature Neurosci. 5: 1288-1293, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12402041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12402041</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12402041" 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/nn968" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="32" class="mim-anchor"></a>
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<a id="Tan1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
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Tan, J., Town, T., Paris, D., Mori, T., Suo, Z., Crawford, F., Mattson, M. P., Flavell, R. A., Mullan, M.
|
|
<strong>Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation.</strong>
|
|
Science 286: 2352-2355, 1999.
|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10600748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10600748</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10600748" 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.286.5448.2352" 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="33" class="mim-anchor"></a>
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<a id="van Zelm2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van Zelm, M. C., Bartol, S. J. W., Driessen, G. J., Mascart, F., Reisli, I., Franco, J. L., Wolska-Kusnierz, B., Kanegane, H., Boon, L., van Dongen, J. J. M., van der Burg, M.
|
|
<strong>Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation.</strong>
|
|
J. Allergy Clin. Immun. 134: 135-144, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24418477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24418477</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24418477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jaci.2013.11.015" 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="34" class="mim-anchor"></a>
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<a id="Varo2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Varo, N., de Lemos, J. A., Libby, P., Morrow, D. A., Murphy, S. A., Nuzzo, R., Gibson, C. M., Cannon, C. P., Braunwald, E., Schonbeck, U.
|
|
<strong>Soluble CD40L: risk prediction after acute coronary syndromes.</strong>
|
|
Circulation 108: 1049-1052, 2003.
|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12912804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12912804</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12912804" 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/10.1161/01.CIR.0000088521.04017.13" 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="35" class="mim-anchor"></a>
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<a id="Wang2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, J., Syrett, C. M., Kramer, M. C., Basu, A., Atchison, M. L., Anguera, M. C.
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<strong>Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X.</strong>
|
|
Proc. Nat. Acad. Sci. 113: E2029-38, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27001848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27001848</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27001848[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=27001848" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.1520113113" 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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Bao Lige - updated : 08/03/2022
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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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Hilary J. Vernon - updated : 07/07/2022<br>Paul J. Converse - updated : 11/5/2015<br>Ada Hamosh - updated : 6/18/2010<br>Paul J. Converse - updated : 4/12/2007<br>Paul J. Converse - updated : 3/2/2007<br>Paul J. Converse - updated : 1/12/2006<br>Marla J. F. O'Neill - updated : 10/12/2005<br>Marla J. F. O'Neill - updated : 1/6/2005<br>Marla J. F. O'Neill - updated : 10/21/2004<br>Patricia A. Hartz - updated : 8/26/2004<br>Victor A. McKusick - updated : 7/16/2003<br>Victor A. McKusick - updated : 4/17/2003
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin : 4/2/2002
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="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 : 04/10/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
|
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 08/03/2022<br>carol : 07/13/2022<br>carol : 07/07/2022<br>alopez : 09/22/2016<br>mgross : 11/06/2015<br>mgross : 11/5/2015<br>alopez : 12/11/2014<br>terry : 4/4/2013<br>alopez : 6/21/2010<br>terry : 6/18/2010<br>terry : 6/18/2010<br>carol : 9/2/2009<br>alopez : 3/18/2008<br>carol : 8/31/2007<br>mgross : 4/13/2007<br>terry : 4/12/2007<br>mgross : 3/8/2007<br>terry : 3/2/2007<br>mgross : 1/12/2006<br>carol : 10/27/2005<br>wwang : 10/14/2005<br>terry : 10/12/2005<br>terry : 8/3/2005<br>carol : 1/10/2005<br>terry : 1/6/2005<br>carol : 10/21/2004<br>mgross : 8/31/2004<br>terry : 8/26/2004<br>cwells : 7/23/2003<br>terry : 7/16/2003<br>ckniffin : 5/15/2003<br>tkritzer : 4/24/2003<br>terry : 4/17/2003<br>alopez : 12/3/2002<br>carol : 10/29/2002<br>ckniffin : 10/28/2002<br>carol : 10/25/2002<br>carol : 4/15/2002<br>ckniffin : 4/15/2002<br>ckniffin : 4/12/2002<br>carol : 4/8/2002<br>ckniffin : 4/5/2002<br>carol : 4/5/2002<br>ckniffin : 4/5/2002
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
|
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<span class="mim-font">
|
|
<strong>*</strong> 300386
|
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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>
|
|
<span class="mim-font">
|
|
|
|
CD40 LIGAND; CD40LG
|
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|
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</span>
|
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</h3>
|
|
</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>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
CD40 ANTIGEN LIGAND; CD40L<br />
|
|
CD154<br />
|
|
TNF-RELATED ACTIVATION PROTEIN; TRAP<br />
|
|
TUMOR NECROSIS FACTOR LIGAND SUPERFAMILY, MEMBER 5; TNFSF5<br />
|
|
GP39
|
|
</span>
|
|
</h4>
|
|
</div>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: CD40LG</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
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<div>
|
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<p>
|
|
<span class="mim-text-font">
|
|
|
|
<strong>SNOMEDCT:</strong> 403835002;
|
|
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</span>
|
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
|
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<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: Xq26.3
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : X:136,648,158-136,660,390 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<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="1">
|
|
<span class="mim-font">
|
|
Xq26.3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Immunodeficiency, X-linked, with hyper-IgM
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
308230
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>The CD40LG gene encodes a transmembrane molecule, CD40 ligand, found on T cells.</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Gauchat et al. (1993) cloned the cDNA for human CD40 ligand (CD40LG) from a CD4-positive T-cell clone. The cDNA predicts a type II membrane protein of 261 amino acids. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Seyama et al. (1996) reported that the CD40LG gene contains 5 exons. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>By virtue of the relation of CD40 ligand to the X-linked hyper-IgM syndrome (HIGM1; 308230), the gene has been mapped to chromosome X. Padayachee et al. (1992, 1993) narrowed the location to Xq26 by multipoint linkage studies demonstrating that it is close to HPRT (308000), a gene that forms part of an extensive YAC contig mapping to Xq26; a maximum lod score of 4.89 was obtained. The existence of an easily scorable VNTR of 5 alleles within the HPRT gene means that other families with X-linked hyper-IgM syndrome are likely to be informative for this polymorphism. </p><p>Aruffo et al. (1993) mapped the GP39 gene to Xq26 by PCR analysis of a regional mapping panel, followed up by fluorescence in situ hybridization for precise localization. By YAC analysis, Pilia et al. (1994) mapped the CD40L locus between DXS144E and DXS300 in Xq26 and determined its transcription to be from 5-prime centromeric to 3-prime telomeric. This corresponded to the site where the clinical phenotype of the hyper-IgM syndrome type 1 had been mapped. </p><p>Allen et al. (1993) mapped the CD40LG gene to the proximal region of the mouse X chromosome, linked to Hprt. Hprt maps to the Xq26-q27.2 region, which suggested that the human CD40LG gene would also map to this region. This was confirmed by fluorescence in situ hybridization studies of CD40LG by Graf et al. (1992) and Allen et al. (1993). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The CD40 ligand molecule aids in stimulating B cells in the immune response. The CD40 molecule (109535) is a glycoprotein expressed on B lymphocytes, epithelial cells, and some carcinoma cells. Crosslinking of CD40 by anti-CD40 monoclonal antibodies mediates B cell proliferation, adhesion, and differentiation (DiSanto et al., 1993; Hollenbaugh et al., 1992). Gauchat et al. (1993) demonstrated by Northern blot and FACS analysis that the human CD40 ligand can be detected on T cells but is absent from B cells and monocytes. It is expressed on both CD4- and CD8-positive T cells. They found that IL4 (147780), an inducer of IgE production, upregulated CD40LG mRNA levels while gamma-interferon (IFNG; 147570), an inhibitor of IgE synthesis, reduced expression of CD40LG mRNA. Thus there appears to be a correlation between human CD40LG expression and IgE production. </p><p>Since CD40 ligand is expressed on platelets and released from them on activation, Heeschen et al. (2003) investigated its predictive value as a marker for clinical outcome and the therapeutic effect of inhibition of glycoprotein IIb (607759)/IIIa receptor (173470) in patients with acute coronary syndromes. Levels of soluble CD40 ligand were elevated in 221 patients with acute coronary syndromes (40.6%). Among patients receiving placebo, elevated soluble CD40 ligand levels indicated a significantly increased risk of death or nonfatal myocardial infarction during 6 months of follow-up. The prognostic value of this marker was validated in patients with chest pain, among whom elevated soluble CD40 ligand levels identified those with acute coronary syndromes who were at high risk for death or nonfatal myocardial infarction. This risk in these patients was reduced by treatment with abciximab, whereas there was no significant treatment effect of abciximab in patients with low levels of soluble CD40 ligand. Heeschen et al. (2003) found that troponin T (191041) and soluble CD40 ligand have independent predictive value with respect to both the risk of ischemic events and the benefit of glycoprotein IIb/IIIa receptor inhibition by abciximab. They speculated that, whereas positivity for troponins may indicate the propensity of the thrombus to embolize, leading to myocardial necrosis, elevated soluble CD40 ligand levels in patients with acute coronary syndromes reflect the inflammatory thrombotic activity of the culprit lesion in recruiting and activating platelets. </p><p>In a cohort of patients with acute coronary syndromes (195 cases, 195 controls), Varo et al. (2003) found that soluble CD40 ligand concentrations above the median were associated with risk for recurrent myocardial infarction or composite death/myocardial infarction within 10 months independent of other predictive variables, including troponin and C-reactive protein (CRP; 123260). Congestive heart failure did not associate with soluble CD40 ligand. Patients with elevated plasma levels of soluble CD40 ligand and troponin showed a markedly increased risk of death or myocardial infarction compared with patients with the lowest levels of both markers (adjusted hazard ratios, 12.1 and 7.2, respectively; p less than 0.01 for both). Varo et al. (2003) stated that these findings support the hypothesis that CD40 ligand plays a central role in the pathophysiology of acute coronary syndromes and validate the report by Heeschen et al. (2003). </p><p>Cipollone et al. (2003) studied 70 patients who underwent percutaneous transluminal coronary angioplasty (PTCA) and had repeat angiograms at 6-month follow-up. They found that patients who developed post-PTCA restenosis had significantly increased levels of CD40L both before the procedure and as long as 6 months after PTCA. Cipollone et al. (2003) also identified preprocedural serum CD40L level as an independent predictor of late lumen loss after PTCA. </p><p>In a study of 25 cigarette smokers and 25 nonsmokers, Harding et al. (2004) found that smokers had increased concentrations of serum C-reactive protein, surface expression of CD40 on monocytes and of CD40L on platelets, and platelet-monocyte aggregates. The level of plasma cotinine, a nicotine metabolite, correlated with monocyte CD40 expression, platelet CD40L expression, and platelet-monocyte aggregates. Harding et al. (2004) concluded that cigarette smokers have upregulation of the CD40/CD40L dyad and platelet-monocyte aggregation that might account for the atherothrombotic consequences of this major cardiovascular risk factor. </p><p>Epstein-Barr virus (EBV), which is implicated in numerous human diseases including lymphoid malignancies, persistently affects peripheral B cells and transforms them into lymphoblastoid cell lines. Imadome et al. (2003) found that EBV equally infects B cells from patients with X-linked hyper-IgM syndrome (308230) and those from healthy donors; however, it hardly transformed X-linked hyper-IgM syndrome B cells because of the dysfunctional CD40L gene of the patients. Unlike CD40, CD40L is usually not expressed on B cells. However, Imadome et al. (2003) found that EBV infection of normal B cells induced CD40L expression as a critical effector in host cell transformation and survival. Moreover, chronic active EBV infection of peripheral T cells, implicated in T cell malignancies, was associated with ectopic expression of CD40. These results suggested that EBV infection induces CD40L/CD40 signaling in host cells, which appears to play an essential role in its persistent infection and malignancies of lymphocytes. </p><p>Bossaller et al. (2006) found that CD40L-deficient patients, like ICOS (604558)-deficient patients, had abrogated germinal center formation and a severe reduction of CXCR5 (BLR1; 601613)-positive T cells. </p><p>Using flow cytometric analysis, van Zelm et al. (2014) found reduced numbers of all memory B-cell subsets except CD27 (TNFRSF7; 186711)-negative/IgA-positive B cells in both CD19 (107265)-deficient patients and CD40L-deficient patients compared with controls. Analysis of transcripts after class switching demonstrated that patient transcripts had fewer somatic mutations and reduced usage of IgG2 and IgA2 subclasses. There was also a deficiency in selection strength of mutations for antigen binding in patients compared with controls, whereas selection to maintain superantigen binding was normal. Selection against the autoreactive properties of immunoglobulins was impaired in patients. Somatic hypermutation analysis revealed decreased AICDA (605257) and UNG (191525) activity in CD40L deficiency, but increased UNG activity and decreased mismatch repair in CD19 deficiency. Van Zelm et al. (2014) concluded that both the B-cell antigen receptor and CD40 signaling pathways are required for selection of immunoglobulin reactivity, but that they differentially mediate DNA repair pathways during somatic hypermutation and thereby together shape the mature B-cell repertoire. </p><p>Wang et al. (2016) showed that chromatin of the inactive X chromosome (Xi) in female mouse and human mature naive T cells lacks the typical heterochromatic modifications of the Xi, resulting in partial reactivation of the Xi and leading to increased expression of immunity-related X-linked genes such as CD40LG and CXCR3 (300574). Analysis of B cells from female patients with systemic lupus erythematosus (SLE) revealed a different X chromosome silencing mechanism compared to controls, which likely caused partial reactivation of the Xi, thereby increasing biallelic expression of autoimmune-associated genes. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 3 of 4 patients with hyper-IgM immunodeficiency syndrome type 1 (HIGM1; 308230), Allen et al. (1993) demonstrated point mutations in the CD40LG gene (300386.0003-300386.0005). Recombinant expression of 2 of the mutant CD40LG cDNAs resulted in proteins incapable of binding to CD40 and unable to induce proliferation or IgE secretion from normal B cells. Activated T cells from the 4 affected patients failed to express wildtype CD40LG, although their B cells responded normally to wildtype CD40LG. Patients with the hyper-IgM syndrome type 1 do not express IgE, strongly indicating that CD40LG is required (in conjunction with IL4) for production of IgE in vivo and suggests that it probably helps induce switching to all other isotypes. Korthauer et al. (1993) likewise followed up on the suggestion of a causal relationship of the condition they symbolized HIGM1 and the gene they symbolized TRAP (for TNF-related activation protein) and demonstrated to be the CD40 ligand. They presented evidence that point mutations in the TRAP gene give rise to nonfunctional or defective expression of TRAP on the surface of T cells in patients with this disorder. DiSanto et al. (1993) found a lack of CD40LG in 4 unrelated boys with the hyper-IgM syndrome type 1. Furthermore, CD40LG transcripts in these patients showed either deletions or point mutations clustered within a limited region of the CD40LG extracellular domain. </p><p>Aruffo et al. (1993) identified point mutations involving the extracellular domain of the gp39 protein in 2 patients with HIGM1. </p><p>See reviews by Kroczek et al. (1994) and Ramesh et al. (1994). Kroczek et al. (1994) tabulated 17 mutations in the CD40L gene that had been identified as the cause of HIGM1. Three of these were different mutations in the same codon, trp140, resulting in a stop signal in 2 cases and in a nonconservative amino acid substitution, trp140-to-gly, in the other (300386.0008). </p><p>Macchi et al. (1995) characterized 9 novel mutations in the CD40LG gene in patients with X-linked hyper-IgM syndrome of various ancestry. They found 2 nonsense mutations, 3 missense mutations, 1 4-bp deletion, and 3 small insertions. One of the nonsense mutations involved a change of codon 140 from TGG to TGA (trp140-to-ter). Trp140-to-ter resulting from a TGG-to-TAG mutation was previously reported (300386.0007). One of the missense mutations involved a change of codon 140 from TGG (trp) to CGG (arg); previously reported was a mutation in codon 140 changing it from TGG (trp) to GGG (gly) (300386.0008). Thus, 4 different point mutations had been observed in codon 140 in patients with the hyper-IgM syndrome type 1, suggesting that it may be a hotspot for mutation. Nonoyama et al. (1997) reported mutations in the CD40 ligand gene in 13 Japanese patients. Nine mutations were novel and included missense, nonsense, splice site, and genomic deletion mutations. Two of the mutations were at trp140, further confirming that codon as a mutation hotspot. </p><p>Lin et al. (1996) succeeded in finding 11 different mutations in all 13 patients whose activated T cells failed to bind a recombinant CD40 construct. The exact nature of 4 of these mutations, a deletion and 3 splice defects, could not be determined by cDNA sequencing. In addition, SSCP analysis permitted rapid carrier detection in 2 families in whom the source of the mutation was most likely a male with gonadal mosaicism who passed the disorder on to some, but not all, of his daughters. </p><p>Using SSCP analysis in the study of the CD40LG gene in affected boys from 19 unrelated families, Katz et al. (1996) identified 16 novel mutations: 6 patients had single base substitutions, 2 patients had single base insertions, 6 patients had deletions ranging from 1 to 7 bases, and 2 patients had large deletions at the 5-prime end of the gene. The mutations were distributed throughout the gene. </p><p>In a study of 30 families, Seyama et al. (1998) identified 28 unique mutations of the CD40LG gene, including 9 missense, 5 nonsense, 9 splice site, and 5 deletion/insertion mutations. </p><p>After screening the entire CD40L gene and identifying 22 single-nucleotide polymorphisms (SNPs), Onouchi et al. (2004) performed an association study with 427 Japanese Kawasaki disease patients and 476 healthy Japanese controls. A SNP in intron 4 (IVS4+121A-G) that was marginally overrepresented in Kawasaki patients was found to be significantly more frequent in male Kawasaki disease patients with coronary artery lesions compared to controls (OR, 2.0; 95% CI, 1.07-3.66; p = 0.030). This SNP was extremely rare in a control Caucasian population (0.7%). Onouchi et al. (2004) suggested that CD40L has a role in the pathogenesis of coronary artery lesions and that this might explain the excess of males affected with Kawasaki disease. </p><p>Palterer et al. (2022) identified a heterozygous missense mutation (M36K; 300386.0015) in the transmembrane domain of the CD40LG gene in a 41-year-old man with HIGM1. The expression of CD40L was reduced on activated T CD4+ cells from the patient. The patient had an atypical clinical presentation that included leishmaniasis and hypogammaglobulinemia. Palterer et al. (2022) concluded that variants in the transmembrane domain of CD40LG act as hypomorphic variants and could lead to atypical clinical features. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Alzheimer disease (104300) has a substantial inflammatory component, and activated microglia may play a central role in neuronal degeneration. Tan et al. (1999) demonstrated that CD40 expression was increased on cultured microglia treated with freshly solubilized amyloid-beta (104760) and on microglia from a transgenic murine model of Alzheimer disease (Tg APPsw). Increased TNF-alpha (191160) production and induction of neuronal injury occurred when amyloid-beta-stimulated microglia were treated with CD40 ligand. Microglia from Tg APPsw mice deficient for CD40 ligand had less activation, suggesting that the CD40-CD40 ligand interaction is necessary for amyloid-beta-induced microglial activation. In addition, abnormal tau (157140) phosphorylation was reduced in Tg APPsw animals deficient for CD40 ligand, suggesting that the CD40-CD40 ligand interaction is an early event in Alzheimer disease pathogenesis. </p><p>In transgenic mice overproducing beta-amyloid but deficient in CD40L, Tan et al. (2002) found decreased astrocytosis and microgliosis associated with diminished beta-amyloid levels and decreased beta-amyloid plaque load. In mice with functional CD40L, anti-CD40L antibody similarly caused marked attenuation of beta-amyloid pathology. In both groups of mice, there was a shift from amyloidogenic to nonamyloidogenic APP processing, suggesting a mechanism by which reduction of available CD40L decreases beta-amyloid pathology. Further evidence suggested an increase in brain-to-blood clearance of beta-amyloid. These results supported a role for the CD40-CD40L interaction in the pathogenesis of amyloid pathology in AD. </p><p>Straw et al. (2003) found that activation of dendritic cells, which was observed during infection of wildtype mice with either the Th2-inducing parasite Schistosoma mansoni or the Th1-inducing parasite Toxoplasma gondii, did not occur in Cd154 -/- mice. The results indicated a major role for CD40-CD154 interaction in maintaining dendritic cell activation during infection, regardless of whether the outcome is a Th1 or a Th2 response. </p><p>McGregor et al. (2004) investigated the role of Cd154 in regulating anti-islet CD8 (see 186910)-positive T cells in a mouse model of type I diabetes (222100), which was generated by islet-specific expression of Tnfa and Cd80 (112203). Their findings indicated that signaling through CD40-CD154 is critical in regulating autoaggressive CD8-positive T cells. This pathway was required to increase regulatory T-cell number and to sensitize autoaggressive T cells to suppression. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Other Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using unbiased transcript profiling in a mouse model of amyotrophic lateral sclerosis (ALS; see 105400), Lincecum et al. (2010) identified a role for the costimulatory pathway, a key regulator of immune responses. Lincecum et al. (2010) observed that this pathway is upregulated in the blood of 56% of human patients with ALS. A therapy using a monoclonal antibody to CD40L was developed that slowed weight loss, delayed paralysis, and extended survival in an ALS mouse model. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>15 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</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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CD40LG, ALA235PRO
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<br />
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SNP: rs104894771,
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ClinVar: RCV000011907
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with hyper-IgM syndrome-1 (HIGM1; 308230), Aruffo et al. (1993) identified a G-to-C transversion at position 724 (numbering according to Hollenbaugh et al., 1992) predicted to result in replacement of ala235 by pro in the cDNA encoding CD40 ligand. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</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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CD40LG, SER128ARG AND GLU129GLY
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<br />
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SNP: rs104894772, rs104894773,
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ClinVar: RCV000011908
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with hype-IgM syndrome-1 (HIGM1; 308230), Aruffo et al. (1993) identified 3 nucleotide changes, a silent change of T to C at position 169, a T to A substitution at position 405, and an A to G substitution at position 407 in the cDNA encoding CD40 ligand. The last 2 changes resulted in the replacement of serine-128 by arginine and glutamic acid-129 by glycine, respectively. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</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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CD40LG, GLY227VAL
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<br />
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SNP: rs104894768,
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ClinVar: RCV000011909
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Allen et al. (1993) identified a substitution of valine for glycine at position 227 of the CD40LG gene in a patient with hyper-IgM syndrome-1 (HIGM1; 308230) (the codons were numbered from the initiating methionine). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</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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CD40LG, LEU155PRO
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<br />
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SNP: rs104894769,
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ClinVar: RCV000011910, RCV001507548
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Allen et al. (1993) identified a substitution of proline for leucine at position 155 of the CD40LG gene in a patient with hyper-IgM syndrome type 1 (HIGM1; 308230). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</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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CD40LG, THR211ASP
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<br />
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ClinVar: RCV000011911
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Allen et al. (1993) identified a substitution of aspartic acid for threonine at position 211 of the CD40LG gene in a patient with hyper-IgM syndrome-1 (HIGM1; 308230). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0006 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</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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CD40LG, MET36ARG
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<br />
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SNP: rs104894774,
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ClinVar: RCV000011912
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a boy with hyper-IgM syndrome-1 (HIGM1; 308230), Korthauer et al. (1993) described a T-to-G transversion of nucleotide 163 converting codon 36 from ATG (met) to AGG (arg). The mutation was located in the part of the gene encoding the transmembrane portion of the CD40 ligand. </p>
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</span>
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</div>
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<div>
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<br />
|
|
</div>
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|
</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CD40LG, TRP140TER
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|
<br />
|
|
|
|
SNP: rs104894775, rs104894776,
|
|
|
|
|
|
|
|
ClinVar: RCV000011913
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy with hyper-IgM syndrome-1 (HIGM1; 308230), Korthauer et al. (1993) identified an amber nonsense mutation: a G-to-A transition of nucleotide 475 changed codon 140 from TGG (trp) to TAG (stop). See also Macchi et al. (1995). </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CD40LG, TRP140GLY
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|
|
<br />
|
|
|
|
SNP: rs104894777,
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|
|
|
|
|
|
|
ClinVar: RCV000011914, RCV000256172
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy with hyper-IgM syndrome-1 (HIGM1; 308230), Korthauer et al. (1993) identified a T-to-G transversion of nucleotide 474 which converted codon 140 from TGG (trp) to GGG (gly). The mutation was located in the part of the gene encoding the extracellular part of the CD40 ligand. See also Macchi et al. (1995). </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CD40LG, 63-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2148552900,
|
|
|
|
|
|
|
|
ClinVar: RCV000011915
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy with hyper-IgM syndrome-1 (HIGM1; 308230), DiSanto et al. (1993) identified a 63-bp (bases 385-447) deletion, removing the 21 amino acid residues from position 116 to 136 of the CD40LG protein. Two other patients showed small deletions (of 8 bp, 300386.0010 and 10 bp, 300386.0011) in precisely the same region of the CD40LG molecule (bases 447-457). DiSanto et al. (1993) hypothesized that the latter 2 patients may have possessed splice site mutations, as the deletions in these cases represented cryptic donor sites. The predicted mutant proteins would be truncated in these 2 cases, 138 amino acids in one, and 144 amino acids in the second, owing to a frameshift, with the introduction of premature stop codons. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CD40LG, 8-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000011916
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient (P2) with hyper-IgM syndrome-1 (HIGM1; 308230), DiSanto et al. (1993) identified a 8-bp deletion in the CD40LG gene. Also see 308230.0009. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CD40LG, 10-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000011917
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient (P4) with hyper-IgM syndrome syndrome-1 (HIGM1; 308230), DiSanto et al. (1993) identified a 10-bp deletion in the CD40LG gene. Also see 308230.0009. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CD40LG, ALA123GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894778,
|
|
|
|
|
|
gnomAD: rs104894778,
|
|
|
|
|
|
ClinVar: RCV000011918
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with hyper-IgM syndrome-1 (HIGM1; 308230), DiSanto et al. (1993) demonstrated a C-to-A transversion at base 407 in a CpG dinucleotide, resulting in change of codon 123 from GCG (ala) to GAG (glu). The same mutation was found in heterozygous state in the mother. The mother was also informative for a polymorphic microsatellite repeat present in the 3-prime untranslated region of the CD40LG gene, thus allowing for the identification of normal and affected CD40LG alleles. Segregation of this CA repeat in sorted CD40LG(+) and CD40LG(-) cell populations in the mother revealed the normal allele in the CD40LG(+) population, whereas the CD40LG(-) population carried the mutant allele. This result indicated that the ala123-to-glu substitution results in a CD40LG molecule that is unable to bind CD40. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CD40LG, 1-BP INS, TTT-TTTT, FS84TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs193922134,
|
|
|
|
|
|
|
|
ClinVar: RCV000011919
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Hyper-IgM syndrome-1 (HIGM1; 308230) was diagnosed on the basis of serum immunoglobulin levels in a 13-year-old boy with sclerosing cholangitis who had received a liver transplant (Kraakman et al., 1995). His brother died at 7 months of age from Pneumocystis carinii pneumonia. Kraakman et al. (1995) demonstrated that the patient had an insertional mutation of an extra T and a run of 4 T's at position 231-234 in the second exon of their cDNA, leading to a frameshift and a premature stop at nucleotide position 297. After translation, a truncated protein would result, containing the first 63 of the 261 CD40L amino acids, followed by 21 unrelated amino acids. The run of T's was flanked by an internally palindromic direct repeat sequence (TTACATGAA) at nucleotide positions 221 and 238, the presence of which may have facilitated the T insertion at position 231. Satisfactory genetic counseling was possible because testing demonstrated that, whereas the patient's mother was a carrier, his clinically normal sister was not a carrier. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CD40LG, ALU INS, EX1
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000011920
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male infant with hyper-IgM syndrome-1 (HIGM1; 308230), Apoil et al. (2007) identified an inactivating mutation in the CD40LG gene resulting from insertion of an AluYb8 element in exon 1. Flow cytometry showed that the mutation led to total deficiency of CD40LG expression in T lymphocytes. The patient's parents and female sib had normal Ig levels. Only 30% of the mother's stimulated T cells expressed CD40LG, compared with 60 to 70% in controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CD40LG, MET36LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894774,
|
|
|
|
|
|
|
|
ClinVar: RCV000480912, RCV001368065
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 41-year-old man with hyper-IgM syndrome-1 (HIGM1; 308230), Palterer et al. (2022) identified a heterozygous c.107T-A transversion in the CD40LG gene, resulting in a met36-to-lys (M36K) substitution in the transmembrane domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was absent in the gnomAD and 1000 Genomes Project databases. The expression of CD40L was reduced on activated T CD4+ cells from the patient. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Allen, R. C., Armitage, R. J., Conley, M. E., Rosenblatt, H., Jenkins, N. A., Copeland, N. G., Bedell, M. A., Edelhoff, S., Disteche, C. M., Simoneaux, D. K., Fanslow, W. C., Belmont, J., Spriggs, M. K.
|
|
<strong>CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome.</strong>
|
|
Science 259: 990-993, 1993.
|
|
|
|
|
|
[PubMed: 7679801]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.7679801]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Apoil, P. A., Kuhlein, E., Robert, A., Rubie, H., Blancher, A.
|
|
<strong>HIGM syndrome caused by insertion of an AluYb8 element in exon 1 of the CD40LG gene.</strong>
|
|
Immunogenetics 59: 17-23, 2007.
|
|
|
|
|
|
[PubMed: 17146684]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s00251-006-0175-5]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Aruffo, A., Farrington, M., Hollenbaugh, D., Li, X., Milatovich, A., Nonoyama, S., Bajorath, J., Grosmaire, L. S., Stenkamp, R., Neubauer, M., Roberts, R. L., Noelle, R. J., Ledbetter, J. A., Francke, U., Ochs, H. D.
|
|
<strong>The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome.</strong>
|
|
Cell 72: 291-300, 1993.
|
|
|
|
|
|
[PubMed: 7678782]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/0092-8674(93)90668-g]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bossaller, L., Burger, J., Draeger, R., Grimbacher, B., Knoth, R., Plebani, A., Durandy, A., Baumann, U., Schlesier, M., Welcher, A. A., Peter, H. H., Warnatz, K.
|
|
<strong>ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells.</strong>
|
|
J. Immun. 177: 4927-4932, 2006.
|
|
|
|
|
|
[PubMed: 16982935]
|
|
|
|
|
|
[Full Text: https://doi.org/10.4049/jimmunol.177.7.4927]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Cipollone, F., Ferri, C., Desideri, G., Paloscia, L., Materazzo, G., Mascellanti, M., Fazia, M., Iezzi, A., Cuccurullo, C., Pini, B., Bucci, M., Santucci, A., Cuccurullo, F., Mezzetti, A.
|
|
<strong>Preprocedural level of soluble CD40L is predictive of enhanced inflammatory response and restenosis after coronary angioplasty.</strong>
|
|
Circulation 108: 2776-2782, 2003.
|
|
|
|
|
|
[PubMed: 14623801]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1161/01.CIR.0000103700.05109.0D]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
DiSanto, J. P., Bonnefoy, J. Y., Gauchat, J. F., Fischer, A., de Saint Basile, G.
|
|
<strong>CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM.</strong>
|
|
Nature 361: 541-543, 1993.
|
|
|
|
|
|
[PubMed: 8094231]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/361541a0]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gauchat, J.-F., Aubry, J.-P., Mazzei, G., Life, P., Jomotte, T., Elson, G., Bonnefoy, J.-Y.
|
|
<strong>Human CD40-ligand: molecular cloning, cellular distribution and regulation of expression by factors controlling IgE production.</strong>
|
|
FEBS Lett. 315: 259-266, 1993.
|
|
|
|
|
|
[PubMed: 7678552]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/0014-5793(93)81175-y]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Graf, D., Korthauer, U., Mages, H. W., Senger, G., Kroczek, R. A.
|
|
<strong>Cloning of TRAP, a ligand for CD40 on human T cells.</strong>
|
|
Europ. J. Immun. 22: 3191-3194, 1992.
|
|
|
|
|
|
[PubMed: 1280226]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/eji.1830221226]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Harding, S. A., Sarma, J., Josephs, D. H., Cruden, N. L., Din, J. N., Twomey, P. J., Fox, K. A. A., Newby, D. E.
|
|
<strong>Upregulation of the CD40/CD40 ligand dyad and platelet-monocyte aggregation in cigarette smokers.</strong>
|
|
Circulation 109: 1926-1929, 2004.
|
|
|
|
|
|
[PubMed: 15078798]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1161/01.CIR.0000127128.52679.E4]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Heeschen, C., Dimmeler, S., Hamm, C. W., van den Brand, M. J., Boersma, E., Zeiher, A. M., Simoons, M. L.
|
|
<strong>Soluble CD40 ligand in acute coronary syndromes.</strong>
|
|
New Eng. J. Med. 348: 1104-1111, 2003.
|
|
|
|
|
|
[PubMed: 12646667]
|
|
|
|
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 08/03/2022<br>Hilary J. Vernon - updated : 07/07/2022<br>Paul J. Converse - updated : 11/5/2015<br>Ada Hamosh - updated : 6/18/2010<br>Paul J. Converse - updated : 4/12/2007<br>Paul J. Converse - updated : 3/2/2007<br>Paul J. Converse - updated : 1/12/2006<br>Marla J. F. O'Neill - updated : 10/12/2005<br>Marla J. F. O'Neill - updated : 1/6/2005<br>Marla J. F. O'Neill - updated : 10/21/2004<br>Patricia A. Hartz - updated : 8/26/2004<br>Victor A. McKusick - updated : 7/16/2003<br>Victor A. McKusick - updated : 4/17/2003
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<span class="mim-text-font">
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Cassandra L. Kniffin : 4/2/2002
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carol : 04/10/2023<br>alopez : 08/03/2022<br>carol : 07/13/2022<br>carol : 07/07/2022<br>alopez : 09/22/2016<br>mgross : 11/06/2015<br>mgross : 11/5/2015<br>alopez : 12/11/2014<br>terry : 4/4/2013<br>alopez : 6/21/2010<br>terry : 6/18/2010<br>terry : 6/18/2010<br>carol : 9/2/2009<br>alopez : 3/18/2008<br>carol : 8/31/2007<br>mgross : 4/13/2007<br>terry : 4/12/2007<br>mgross : 3/8/2007<br>terry : 3/2/2007<br>mgross : 1/12/2006<br>carol : 10/27/2005<br>wwang : 10/14/2005<br>terry : 10/12/2005<br>terry : 8/3/2005<br>carol : 1/10/2005<br>terry : 1/6/2005<br>carol : 10/21/2004<br>mgross : 8/31/2004<br>terry : 8/26/2004<br>cwells : 7/23/2003<br>terry : 7/16/2003<br>ckniffin : 5/15/2003<br>tkritzer : 4/24/2003<br>terry : 4/17/2003<br>alopez : 12/3/2002<br>carol : 10/29/2002<br>ckniffin : 10/28/2002<br>carol : 10/25/2002<br>carol : 4/15/2002<br>ckniffin : 4/15/2002<br>ckniffin : 4/12/2002<br>carol : 4/8/2002<br>ckniffin : 4/5/2002<br>carol : 4/5/2002<br>ckniffin : 4/5/2002
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