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<title>
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Entry
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- *123890 - CYTOTOXIC T LYMPHOCYTE-ASSOCIATED 4; CTLA4
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- OMIM
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</ul>
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</nav>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="row">
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<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
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<div class="form-group">
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<li role="separator" class="divider"></li>
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<a href="/history"> Search History </a>
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</form>
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<div class="row">
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<p />
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*123890</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<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="#biochemicalFeatures">Biochemical Features</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>
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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>
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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/123890">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>
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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=ENSG00000163599;t=ENST00000648405" 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=1493" 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=123890" 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=ENSG00000163599;t=ENST00000648405" 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_001037631,NM_005214" 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_005214" 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=123890" 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=00474&isoform_id=00474_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/CTLA4" 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/184787,291929,553245,4099841,6049193,13128929,15778586,17646228,19744771,21361212,27549581,27735177,46854814,47125341,49902519,49904741,55824380,62702250,62768599,83700231,84872760,110626492,110626494,110681873,119590760,189053966,229617465,319739997,319740001,319740003,319740005" 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/P16410" 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=1493" 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=ENSG00000163599;t=ENST00000648405" 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=CTLA4" 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=CTLA4" 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+1493" 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/CTLA4" 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:1493" 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/1493" 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=chr2&hgg_gene=ENST00000648405.2&hgg_start=203867771&hgg_end=203873965&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:2505" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=123890[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=123890[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000163599" 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=CTLA4" 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=CTLA4" 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=CTLA4" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=CTLA4&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/PA27006" 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:2505" 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:88556" 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/CTLA4#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:88556" 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/1493/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=1493" 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>
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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:1493" 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=CTLA4&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> 1197361002<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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123890
|
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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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CYTOTOXIC T LYMPHOCYTE-ASSOCIATED 4; CTLA4
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
CD152
|
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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>
|
|
<br />
|
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</div>
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<div>
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<a id="includedTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
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</p>
|
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</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
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CYTOTOXIC T LYMPHOCYTE-ASSOCIATED 4, SOLUBLE ISOFORM, INCLUDED
|
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</span>
|
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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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CTLA4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CTLA4</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/2/934?start=-3&limit=10&highlight=934">2q33.2</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:203867771-203873965&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'})">2:203,867,771-203,873,965</a> </span>
|
|
</em>
|
|
</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>
|
|
<br />
|
|
</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
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|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=609755,601388,140300,152700,616100" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
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|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
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<li><a href="/graph/radial/123890" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>CTLA4 is a member of the immunoglobulin superfamily and is a costimulatory molecule expressed by activated T cells. CTLA4 is similar to the T-cell costimulatory CD28 (<a href="/entry/186760">186760</a>), and both molecules bind to B7-1 (CD80; <a href="/entry/112203">112203</a>) and B7-2 (CD86; <a href="/entry/601020">601020</a>) on antigen-presenting cells. CTLA4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal (<a href="#29" class="mim-tip-reference" title="Magistrelli, G., Jeannin, P., Herbault, N., Benoit de Coignac, A., Gauchat, J.-F., Bonnefoy, J.-Y., Delneste, Y. <strong>A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells.</strong> Europ. J. Immun. 29: 3596-3602, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10556814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10556814</a>] [<a href="https://doi.org/10.1002/(SICI)1521-4141(199911)29:11<3596::AID-IMMU3596>3.0.CO;2-Y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10556814">Magistrelli et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10556814" 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="#8" class="mim-tip-reference" title="Dariavach, P., Mattei, M.-G., Golstein, P., Lefranc, M.-P. <strong>Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains.</strong> Europ. J. Immun. 18: 1901-1905, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3220103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3220103</a>] [<a href="https://doi.org/10.1002/eji.1830181206" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3220103">Dariavach et al. (1988)</a> used a mouse Ctla4 probe to isolate a partial sequence for the human CTLA4 gene from a genomic cDNA library. The predicted protein shares 76% overall homology and complete identity in the cytoplasmic domain with the mouse protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3220103" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Harper, K., Balzano, C., Rouvier, E., Mattei, M.-G., Luciani, M.-F., Golstein, P. <strong>CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location.</strong> J. Immun. 147: 1037-1044, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1713603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1713603</a>]" pmid="1713603">Harper et al. (1991)</a> isolated several cDNA clones corresponding to the human CTLA4 gene from a stimulated peripheral blood cell human cDNA library. The putative protein contains a leader sequence, a V domain, a transmembrane domain, and a cytoplasmic tail encoded by 4 exons, respectively. The cytoplasmic tail contains 2 potential phosphorylation sites. Northern blot analysis detected 2 CTLA4 mRNA transcripts of 1.8 and 0.8 kb in activated peripheral blood T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1713603" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Linsley, P. S., Nadler, S. G., Bajorath, J., Peach, R., Leung, H. T., Rogers, J., Bradshaw, J., Stebbins, M., Leytze, G., Brady, W., Malacko, A. R., Marquardt, H., Shaw, S.-Y. <strong>Binding stoichiometry of the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) : a disulfide-linked homodimer binds two CD86 molecules.</strong> J. Biol. Chem. 270: 15417-15424, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7541042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7541042</a>] [<a href="https://doi.org/10.1074/jbc.270.25.15417" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7541042">Linsley et al. (1995)</a> demonstrated that the CTLA4 protein is a homodimer interconnected by a disulfide bond in the extracellular domain at cysteine residue 120. Each monomeric polypeptide contains a high affinity binding site for the costimulatory molecules B7-1 and B7-2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7541042" 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="Ling, V., Wu, P. W., Finnerty, H. F., Sharpe, A. H., Gray, G. S., Collins, M. <strong>Complete sequence determination of the mouse and human CTLA4 gene loci: cross-species DNA sequence similarity beyond exon borders.</strong> Genomics 60: 341-355, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10493833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10493833</a>] [<a href="https://doi.org/10.1006/geno.1999.5930" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10493833">Ling et al. (1999)</a> reported the complete revised sequence of the human and mouse CTLA4 genes. The deduced 223-amino acid human protein shows high homology to the mouse protein. There are also similarities in noncoding regions, suggesting conserved transcriptional control. Northern blot analysis detected multiple human transcripts of 1, 2.4, 5, and 7 kb at high levels in spleen, thymus, and peripheral blood leukocytes; lesser expression of the 2.4- and 5-kb transcripts was detected in multiple tissues, including testis, uterus, colon, heart, and brain. The authors suggested that the signals in organ tissues may reflect passenger lymphocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10493833" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using RT-PCR, <a href="#29" class="mim-tip-reference" title="Magistrelli, G., Jeannin, P., Herbault, N., Benoit de Coignac, A., Gauchat, J.-F., Bonnefoy, J.-Y., Delneste, Y. <strong>A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells.</strong> Europ. J. Immun. 29: 3596-3602, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10556814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10556814</a>] [<a href="https://doi.org/10.1002/(SICI)1521-4141(199911)29:11<3596::AID-IMMU3596>3.0.CO;2-Y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10556814">Magistrelli et al. (1999)</a> found that nonactivated human peripheral blood T lymphocytes expressed an alternatively spliced form of CTLA4. The splicing induces deletion of the transmembrane region encoded by exon 2, resulting in the production of a soluble form of the protein with a molecular mass of 23 kD; membrane CTLA4 has an apparent molecular mass of 45 kD, suggesting that the soluble form is a monomeric protein. Functional studies showed that the soluble form of CTLA4 is downregulated by T-cell activation, in contrast to membrane CTLA4, which is upregulated by T-cell activation. The authors found the soluble form of CTLA4 in sera from 14 of 64 healthy subjects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10556814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Oaks, M. K., Hallett, K. M., Penwell, R. T., Stauber, E. C., Warren, S. J., Tector, A. J. <strong>A native soluble form of CTLA-4.</strong> Cell. Immun. 201: 144-153, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10831323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10831323</a>] [<a href="https://doi.org/10.1006/cimm.2000.1649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10831323">Oaks et al. (2000)</a> reported that the 137-amino acid CTLA4 variant, which they called sCTLA4 (soluble CTLA4), has the same sequence as the extracellular portion of the full-length molecule (CTLA4-TM), but contains only 22 of its 34 cytoplasmic residues. RT-PCR analysis of rat tissues detected both forms of CTLA4 in lymph node, spleen, and peripheral blood, only CTLA4-TM in adult thymus, only sCTLA4 in bone marrow cells, and neither form in nonlymphoid tissues. Within T-cell subsets, equivalent amounts of both forms were detected in CD4+ (<a href="/entry/186940">186940</a>) cells, but CTLA4-TM was 2.5-fold greater in CD8+ T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10831323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By flow cytometric analysis, <a href="#19" class="mim-tip-reference" title="Kaufmann, D. E., Kavanagh, D. G., Pereyra, F., Zaunders, J. J., Mackey, E. W., Miura, T., Palmer, S., Brockman, M., Rathod, A., Piechocka-Trocha, A., Baker, B., Zhu, B., and 9 others. <strong>Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction.</strong> Nature Immun. 8: 1246-1254, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17906628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17906628</a>] [<a href="https://doi.org/10.1038/ni1515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17906628">Kaufmann et al. (2007)</a> showed that CTLA4 expression was selectively upregulated in human immunodeficiency virus-1 (HIV-1; see <a href="/entry/609423">609423</a>)-specific CD4-positive T cells, but not in CD8-positive T cells or control cytomegalovirus-specific CD4-positive T cells, in all categories of HIV-infected subjects tested except those with extremely low viral loads in the absence of antiretroviral therapy (elite controllers). CTLA4 expression correlated positively with disease progression and negatively with the capacity of CD4-positive T cells to express IL2 (<a href="/entry/147680">147680</a>). Nearly all HIV-specific CD4-positive T cells from patients with progressive disease coexpressed CTLA4 with PD1 (PDCD1; <a href="/entry/600244">600244</a>), whereas just over half of HIV-specific CD4-positive T cells from elite controllers did so. Blockade of CTLA4 expression in vitro augmented HIV-specific CD4-positive T-cell function. <a href="#19" class="mim-tip-reference" title="Kaufmann, D. E., Kavanagh, D. G., Pereyra, F., Zaunders, J. J., Mackey, E. W., Miura, T., Palmer, S., Brockman, M., Rathod, A., Piechocka-Trocha, A., Baker, B., Zhu, B., and 9 others. <strong>Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction.</strong> Nature Immun. 8: 1246-1254, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17906628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17906628</a>] [<a href="https://doi.org/10.1038/ni1515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17906628">Kaufmann et al. (2007)</a> proposed that this reversible immunoregulatory pathway, which is selectively associated with CD4-positive T-cell dysfunction, may be an immunotherapeutic target. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17906628" 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="#14" class="mim-tip-reference" title="Harper, K., Balzano, C., Rouvier, E., Mattei, M.-G., Luciani, M.-F., Golstein, P. <strong>CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location.</strong> J. Immun. 147: 1037-1044, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1713603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1713603</a>]" pmid="1713603">Harper et al. (1991)</a> and <a href="#25" class="mim-tip-reference" title="Ling, V., Wu, P. W., Finnerty, H. F., Sharpe, A. H., Gray, G. S., Collins, M. <strong>Complete sequence determination of the mouse and human CTLA4 gene loci: cross-species DNA sequence similarity beyond exon borders.</strong> Genomics 60: 341-355, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10493833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10493833</a>] [<a href="https://doi.org/10.1006/geno.1999.5930" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10493833">Ling et al. (1999)</a> determined that the CTLA4 gene contains 4 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10493833+1713603" 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="#8" class="mim-tip-reference" title="Dariavach, P., Mattei, M.-G., Golstein, P., Lefranc, M.-P. <strong>Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains.</strong> Europ. J. Immun. 18: 1901-1905, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3220103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3220103</a>] [<a href="https://doi.org/10.1002/eji.1830181206" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3220103">Dariavach et al. (1988)</a> reported that human CTLA4 maps to chromosome 2q33. By study of yeast artificial chromosomes, <a href="#5" class="mim-tip-reference" title="Buonavista, N., Balzano, C., Pontarotti, P., Le Paslier, D., Golstein, P. <strong>Molecular linkage of the human CTLA4 and CD28 Ig-superfamily genes in yeast artificial chromosomes.</strong> Genomics 13: 856-861, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1322357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1322357</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90169-s" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1322357">Buonavista et al. (1992)</a> demonstrated that the human CD28 (<a href="/entry/186760">186760</a>) and CTLA4 genes are in the same fragment, indicating that they are separated by only 25 to 150 kb; a CpG island was found between these genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1322357+3220103" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Harper, K., Balzano, C., Rouvier, E., Mattei, M.-G., Luciani, M.-F., Golstein, P. <strong>CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location.</strong> J. Immun. 147: 1037-1044, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1713603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1713603</a>]" pmid="1713603">Harper et al. (1991)</a> mapped the mouse Ctla4 gene to chromosome 1 by in situ hybridization. By means of intersubspecific backcrosses, <a href="#16" class="mim-tip-reference" title="Howard, T. A., Rochelle, J. M., Seldin, M. F. <strong>Cd28 and Ctla-4, two related members of the Ig supergene family, are tightly linked on proximal mouse chromosome 1.</strong> Immunogenetics 33: 74-76, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671668</a>] [<a href="https://doi.org/10.1007/BF00211698" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1671668">Howard et al. (1991)</a> demonstrated that mouse Ctla4 is located in the proximal part of chromosome 1. It is closely linked to Cd28; no recombinations were detected in 114 meiotic events examined. The authors noted that Cd28 and Ctla4 are related members of the Ig supergene family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1671668+1713603" 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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CTLA4 binds to the B7 isoforms with an affinity that is 10 to 100 times that of CD28. <a href="#35" class="mim-tip-reference" title="Ostrov, D. A., Shi, W., Schwartz, J.-C. D., Almo, S. C., Nathenson, S. G. <strong>Structure of murine CTLA-4 and its role in modulating T cell responsiveness.</strong> Science 290: 816-819, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11052947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11052947</a>] [<a href="https://doi.org/10.1126/science.290.5492.816" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11052947">Ostrov et al. (2000)</a> determined the crystal structure of the extracellular portion of murine Ctla4 at 2.0-angstrom resolution. Consistent with its membership in the Ig superfamily, Ctla4 displays a strand topology similar to V-alpha domains. Ctla4 has an unusual dimerization mode that places the B7 binding sites distal to the dimerization interface, allowing each Ctla4 dimer to bind 2 divalent B7 molecules. The authors suggested that periodic rearrangement of these components might explain the role of CTLA4 in the regulation of T-cell responsiveness. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11052947" 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="#44" class="mim-tip-reference" title="Stamper, C. C., Zhang, Y., Tobin, J. F., Erbe, D. V., Ikemizu, S., Davis, S. J., Stahl, M. L., Seehra, J., Somers, W. S., Mosyak, L. <strong>Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses.</strong> Nature 410: 608-611, 2001. Note: Erratum: Nature 411: 617 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11279502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11279502</a>] [<a href="https://doi.org/10.1038/35069118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11279502">Stamper et al. (2001)</a> reported the crystal structure of the human CTLA4/B7.1 costimulatory complex at 3.0-angstrom resolution. They stated that the relatively small binding complex exhibits an unusually high degree of shape complementarity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11279502" 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="#42" class="mim-tip-reference" title="Schwartz, J.-C. D., Zhang, X., Fedorov, A. A., Nathenson, S. G., Almo, S. C. <strong>Structural basis for co-stimulation by the human CTLA-4/B7-2 complex.</strong> Nature 410: 604-608, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11279501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11279501</a>] [<a href="https://doi.org/10.1038/35069112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11279501">Schwartz et al. (2001)</a> reported the crystal structure of the complex between the disulfide-linked homodimer of human CTLA4 and the receptor-binding domain of human B7-2 at 3.2-angstrom resolution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11279501" 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="#33" class="mim-tip-reference" title="Oaks, M. K., Hallett, K. M., Penwell, R. T., Stauber, E. C., Warren, S. J., Tector, A. J. <strong>A native soluble form of CTLA-4.</strong> Cell. Immun. 201: 144-153, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10831323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10831323</a>] [<a href="https://doi.org/10.1006/cimm.2000.1649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10831323">Oaks et al. (2000)</a> found that activation of human lymphocytes resulted in the disappearance of sCTLA4 at 48 hours followed by its gradual reappearance, whereas CTLA4-TM rapidly increased and remained present at the same level after activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10831323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Oaks, M. K., Hallett, K. M. <strong>Cutting edge: a soluble form of CTLA-4 in patients with autoimmune thyroid disease.</strong> J. Immun. 164: 5015-5018, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10799854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10799854</a>] [<a href="https://doi.org/10.4049/jimmunol.164.10.5015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10799854">Oaks and Hallett (2000)</a> identified sCTLA4 in only 1 of 30 normal subjects but in 11 of 20 patients with autoimmune thyroiditis (8 of 17 with Graves disease (<a href="/entry/275000">275000</a>) and 3 of 3 with Hashimoto disease (<a href="/entry/140300">140300</a>)). The data indicated that sCTLA4 represents an intact functional receptor for CD80 (<a href="/entry/112203">112203</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10799854" 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>CTLA4Ig is a soluble chimeric protein consisting of the extracellular domain of human CTLA4 and a fragment of the Fc portion of human IgG1 (<a href="/entry/147100">147100</a>). It binds to B7-1 and to B7-2 molecules on antigen-presenting cells (APCs) and thereby blocks the CD28-mediated costimulatory signal for T-cell activation. Biologic activity of CTLA4Ig was demonstrated in a variety of animal models of transplantation (<a href="#39" class="mim-tip-reference" title="Sayegh, M. H., Turka, L. A. <strong>The role of T-cell costimulatory activation pathways in transplant rejection.</strong> New Eng. J. Med. 338: 1813-1821, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9632449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9632449</a>] [<a href="https://doi.org/10.1056/NEJM199806183382506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9632449">Sayegh and Turka, 1998</a>) and autoimmunity (<a href="#38" class="mim-tip-reference" title="Reiser, H., Stadecker, M. J. <strong>Costimulatory B7 molecules in the pathogenesis of infectious and autoimmune diseases.</strong> New Eng. J. Med. 335: 1369-1377, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8857022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8857022</a>] [<a href="https://doi.org/10.1056/NEJM199610313351807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8857022">Reiser and Stadecker, 1996</a>). In 43 patients with stable psoriasis vulgaris (<a href="/entry/177900">177900</a>), <a href="#1" class="mim-tip-reference" title="Abrams, J. R., Lebwohl, M. G., Guzzo, C. A., Jegasothy, B. V., Goldfarb, M. T., Goffe, B. S., Menter, A., Lowe, N. J., Krueger, G., Brown, M. J., Weiner, R. S., Birkhofer, M. J., Warner, G. L., Berry, K. K., Linsley, P. S., Krueger, J. G., Ochs, H. D., Kelley, S. L., Kang, S. <strong>CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris.</strong> J. Clin. Invest. 103: 1243-1252, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10225967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10225967</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10225967[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI5857" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10225967">Abrams et al. (1999)</a> administered 4 infusions of CTLA4Ig. A 50% or greater sustained improvement in clinical disease activity was achieved in 46% of patients, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. There was no markedly increased rate of intralesional T-cell apoptosis, suggesting that the decreased number of lesional T cells was probably attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. The findings illustrated the importance of the CD28/CTLA4 pathway in the pathogenesis of psoriasis and suggested a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9632449+10225967+8857022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Grohmann, U., Orabona, C., Fallarino, F., Vacca, C., Calcinaro, F., Falorni, A., Candeloro, P., Belladonna, M. L., Bianchi, R., Fioretti, M. C., Puccetti, P. <strong>CTLA-4-Ig regulates tryptophan catabolism in vivo.</strong> Nature Immun. 3: 1097-1101, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12368911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12368911</a>] [<a href="https://doi.org/10.1038/ni846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12368911">Grohmann et al. (2002)</a> noted that Ctla4-Ig fusion protein blocked allograft and xenograft rejection in models of cardiac, liver, and pancreatic islet transplantation, but that B7 expression was required in cardiac donor cells. They hypothesized that, after binding, both Ctla4 and B7 are activated, changing the functional state of both the T cell and the antigen-presenting cell. <a href="#13" class="mim-tip-reference" title="Grohmann, U., Orabona, C., Fallarino, F., Vacca, C., Calcinaro, F., Falorni, A., Candeloro, P., Belladonna, M. L., Bianchi, R., Fioretti, M. C., Puccetti, P. <strong>CTLA-4-Ig regulates tryptophan catabolism in vivo.</strong> Nature Immun. 3: 1097-1101, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12368911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12368911</a>] [<a href="https://doi.org/10.1038/ni846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12368911">Grohmann et al. (2002)</a> found that in the presence of the indoleamine 2,3-dioxygenase (IDO; <a href="/entry/147435">147435</a>) inhibitor, 1-methyltryptophan (1MT), Ctla4-Ig was unable to promote engraftment of islet cells in mice. In vitro, Ctla4Ig treatment resulted in an increased rate of tryptophan degradation to kynurenine to an extent similar to that induced by gamma-interferon (IFNG; <a href="/entry/147570">147570</a>) and required the presence of B7 molecules on dendritic cells (DCs). Indeed, DCs expressing B7 produced enhanced levels of Ifng, but not Tnf, in response to Ctla4 ligation. Expression of both Ifng and Stat1 (<a href="/entry/600555">600555</a>) was required for kynurenine production and Ctla4 suppression of the rejection response, suggesting that Ifng can act on tolerogenic DCs in an autocrine or paracrine manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12368911" 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>CD4 (<a href="/entry/186940">186940</a>)-positive/CD25 (<a href="/entry/147730">147730</a>)-positive regulatory T cells (Tregs) exert control over the immune response by interacting with APCs, particularly DCs. <a href="#11" class="mim-tip-reference" title="Fallarino, F., Grohmann, U., Hwang, K. W., Orabona, C., Vacca, C., Bianchi, R., Belladonna, M. L., Fioretti, M. C., Alegre, M.-L., Puccetti, P. <strong>Modulation of tryptophan catabolism by regulatory T cells.</strong> Nature Immun. 4: 1206-1212, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14578884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14578884</a>] [<a href="https://doi.org/10.1038/ni1003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14578884">Fallarino et al. (2003)</a> showed that mouse Cd4+/Cd25+ Tregs expressing Ctla4 conditioned B7-expressing DCs to express Ido and produce Ifng. DCs conditioned in vitro by Tregs mediated suppressive effects in vivo that were dependent on effective tryptophan catabolism. The requirement for Ctla4 expression was overcome in Tregs stimulated with lipopolysaccharide to produce substantial amounts of Ifng and interleukin-10 (IL10; <a href="/entry/124092">124092</a>). <a href="#11" class="mim-tip-reference" title="Fallarino, F., Grohmann, U., Hwang, K. W., Orabona, C., Vacca, C., Bianchi, R., Belladonna, M. L., Fioretti, M. C., Alegre, M.-L., Puccetti, P. <strong>Modulation of tryptophan catabolism by regulatory T cells.</strong> Nature Immun. 4: 1206-1212, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14578884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14578884</a>] [<a href="https://doi.org/10.1038/ni1003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14578884">Fallarino et al. (2003)</a> concluded that Tregs prime DCs for tolerance induction through IDO-based immunoregulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14578884" 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 in vitro migration assays and in vivo 2-photon laser scanning microscopy, <a href="#40" class="mim-tip-reference" title="Schneider, H., Downey, J., Smith, A., Zinselmeyer, B. H., Rush, C., Brewer, J. M., Wei, B., Hogg, N., Garside, P., Rudd, C. E. <strong>Reversal of the TCR stop signal by CTLA-4.</strong> Science 313: 1972-1975, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16931720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16931720</a>] [<a href="https://doi.org/10.1126/science.1131078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16931720">Schneider et al. (2006)</a> showed that CTLA4 increases T-cell motility and overrides the T-cell receptor (TCR)-induced stop signal required for stable conjugate formation between T cells and antigen-presenting cells. This event led to reduced contact periods between T cells and antigen-presenting cells that in turn decreased cytokine production and proliferation. <a href="#40" class="mim-tip-reference" title="Schneider, H., Downey, J., Smith, A., Zinselmeyer, B. H., Rush, C., Brewer, J. M., Wei, B., Hogg, N., Garside, P., Rudd, C. E. <strong>Reversal of the TCR stop signal by CTLA-4.</strong> Science 313: 1972-1975, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16931720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16931720</a>] [<a href="https://doi.org/10.1126/science.1131078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16931720">Schneider et al. (2006)</a> concluded that their results suggested a fundamentally different model of reverse stop signaling, by which CTLA4 modulates the threshold for T-cell activation and protects against autoimmunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16931720" 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>CTLA4 shares 2 ligands, CD80 and CD86 (<a href="/entry/601020">601020</a>), with a stimulatory receptor, CD28 (<a href="/entry/186760">186760</a>). <a href="#36" class="mim-tip-reference" title="Qureshi, O. S., Zheng, Y., Nakamura, K., Attridge, K., Manzotti, C., Schmidt, E. M., Baker, J., Jeffery, L. E., Kaur, S., Briggs, Z., Hou, T. Z., Futter, C. E., Anderson, G., Walker, L. S. K., Sansom, D. M. <strong>Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.</strong> Science 332: 600-603, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21474713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21474713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21474713[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1202947" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21474713">Qureshi et al. (2011)</a> showed that CTLA4 can capture its ligands and CD86 from opposing cells by a process of trans-endocytosis. After removal, these costimulatory ligands are degraded inside CTLA4-expressing cells, resulting in impaired costimulation via CD28. Acquisition of CD86 from antigen-presenting cells is stimulated by T cell receptor engagement and observed in vitro and in vivo. <a href="#36" class="mim-tip-reference" title="Qureshi, O. S., Zheng, Y., Nakamura, K., Attridge, K., Manzotti, C., Schmidt, E. M., Baker, J., Jeffery, L. E., Kaur, S., Briggs, Z., Hou, T. Z., Futter, C. E., Anderson, G., Walker, L. S. K., Sansom, D. M. <strong>Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.</strong> Science 332: 600-603, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21474713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21474713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21474713[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1202947" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21474713">Qureshi et al. (2011)</a> concluded that their data revealed a mechanism of immune regulation in which CTLA4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands, accounting for many of the features of the CD28-CTLA4 system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21474713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Chain, J. L., Martin, A. K., Mack, D. G., Maier, L. A., Palmer, B. E., Fontenot, A. P. <strong>Impaired function of CTLA-4 in the lungs of patients with chronic beryllium disease contributes to persistent inflammation.</strong> J. Immun. 191: 1648-1656, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23851684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23851684</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23851684[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/10.4049/jimmunol.1300282" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23851684">Chain et al. (2013)</a> examined blood and bronchoalveolar lavage cells from individuals with chronic beryllium disease (CBD) and detected increased CTLA4 expression on CD4-positive T cells in lung compared with blood. CTLA4 expression was highest in beryllium-responsive CD4-positive T cells that retained proliferative ability and that expressed IL2. Induction of CTLA4 signaling in blood cells inhibited beryllium-induced T-cell proliferation, but it had no effect on the ability of lung cells to respond to beryllium. <a href="#6" class="mim-tip-reference" title="Chain, J. L., Martin, A. K., Mack, D. G., Maier, L. A., Palmer, B. E., Fontenot, A. P. <strong>Impaired function of CTLA-4 in the lungs of patients with chronic beryllium disease contributes to persistent inflammation.</strong> J. Immun. 191: 1648-1656, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23851684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23851684</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23851684[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/10.4049/jimmunol.1300282" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23851684">Chain et al. (2013)</a> concluded that loss of CD28 on beryllium-responsive CD4-positive T cells and the resultant ineffective CTLA4 pathway in lung contribute to persistent inflammation in CBD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23851684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Lo, B., Zhang, K., Lu, W., Zheng, L., Zhang, Q., Kanellopoulou, C., Zhang, Y., Liu, Z., Fritz, J. M., Marsh, R., Husami, A., Kissell, D., and 21 others. <strong>Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy.</strong> Science 349: 436-440, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26206937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26206937</a>] [<a href="https://doi.org/10.1126/science.aaa1663" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26206937">Lo et al. (2015)</a> found that LRBA (<a href="/entry/606453">606453</a>) regulates CTLA4 expression. LRBA colocalizes with CTLA4 in endosomal vesicles, and LRBA deficiency or knockdown increased CTLA4 turnover, which resulted in reduced levels of CTLA4 protein in FOXP3+ regulatory and activated conventional T cells. In LRBA-deficient cells, inhibition of lysosome degradation with chloroquine prevented CTLA4 loss. <a href="#27" class="mim-tip-reference" title="Lo, B., Zhang, K., Lu, W., Zheng, L., Zhang, Q., Kanellopoulou, C., Zhang, Y., Liu, Z., Fritz, J. M., Marsh, R., Husami, A., Kissell, D., and 21 others. <strong>Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy.</strong> Science 349: 436-440, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26206937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26206937</a>] [<a href="https://doi.org/10.1126/science.aaa1663" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26206937">Lo et al. (2015)</a> concluded that their observations elucidated a mechanism for CTLA4 trafficking and control of immune responses and suggested therapies for diseases involving the CTLA4 pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26206937" 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="#50" class="mim-tip-reference" title="Vetizou, M., Pitt, J. M., Daillere, R., Lepage, P., Waldschmitt, N., Flament, C., Rusakiewicz, S., Routy, B., Roberti, M. P., Duong, C. P. M., Poirier-Colame, V., Roux, A., and 26 others. <strong>Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.</strong> Science 350: 1079-1084, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26541610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26541610</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26541610[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aad1329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26541610">Vetizou et al. (2015)</a> found that the antitumor effects of CTLA4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA4 blockade. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26541610" 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="#32" class="mim-tip-reference" title="Nistico, L., Buzzetti, R., Pritchard, L. E., Van der Auwera, B., Giovannini, C., Bosi, E., Martinez Larrad, M. T., Serrano Rios, M., Chow, C. C., Cockram, C. S., Jacobs, K., Mijovic, C., Bain, S. C., Barnett, A. H., Vandewalle, C. L., Schuit, F., Gorus, F. K., Belgian Diabetes Registry, Tosi, R., Pozzilli, P., Todd, J. A. <strong>The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes.</strong> Hum. Molec. Genet. 5: 1075-1080, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8817351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8817351</a>] [<a href="https://doi.org/10.1093/hmg/5.7.1075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8817351">Nistico et al. (1996)</a> identified a 49A-G transition polymorphism in exon 1 of the CTLA4 gene, resulting in a thr17-to-ala (T17A; <a href="#0001">123890.0001</a>) substitution in the leader peptide of the protein. Among 529 Belgian control individuals, the frequencies for the 49A and 49G alleles were 68% and 32%, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8817351" 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="#47" class="mim-tip-reference" title="Ueda, H., Howson, J. M. M., Esposito, L., Heward, J., Snook, H., Chamberlain, G., Rainbow, D. B., Hunter, K. M. D., Smith, A. N., DiGenova, G., Herr, M. H., Dahlman, I., and 41 others. <strong>Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease.</strong> Nature 423: 506-511, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12724780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12724780</a>] [<a href="https://doi.org/10.1038/nature01621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12724780">Ueda et al. (2003)</a> identified a series of single-nucleotide polymorphisms (SNPs) between 0.2 and 6.3 kb 3-prime of the end of the CTLA4 transcript. They found that one, termed CT60 (<a href="#0002">123890.0002</a>), encodes either a protective A/A genotype or a predisposing G/G genotype for autoimmune disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12724780" 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="#57" class="mim-tip-reference" title="Zhernakova, A., Eerligh, P., Barrera, P., Wesoly, J. Z., Huizinga, T. W. J., Roep, B. O., Wijmenga, C., Koeleman, B. P. C. <strong>CTLA4 is differentially associated with autoimmune diseases in the Dutch population.</strong> Hum. Genet. 118: 58-66, 2005. Note: Erratum: Hum. Genet. 119: 225 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16025348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16025348</a>] [<a href="https://doi.org/10.1007/s00439-005-0006-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16025348">Zhernakova et al. (2005)</a> tested CTLA4 gene polymorphisms for association in 350 Dutch patients with type 1 diabetes (T1D12; <a href="/entry/601388">601388</a>), 310 with celiac disease (see <a href="/entry/609755">609755</a>), 520 with rheumatoid arthritis (see <a href="/entry/180300">180300</a>), and 900 controls. They found a significant association between so-called CTLA4 haplotype 2 and type 1 diabetes, and between CTLA4 haplotype 3 and early-onset celiac disease, but no association between CTLA4 haplotype and rheumatoid arthritis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16025348" 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>For discussion of a possible association between variation in the CTLA4 gene and susceptibility to rheumatoid arthritis, see <a href="/entry/180300">180300</a>.</p><p><strong><em>Type 1 Diabetes Mellitus 12</em></strong></p><p>
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<a href="#32" class="mim-tip-reference" title="Nistico, L., Buzzetti, R., Pritchard, L. E., Van der Auwera, B., Giovannini, C., Bosi, E., Martinez Larrad, M. T., Serrano Rios, M., Chow, C. C., Cockram, C. S., Jacobs, K., Mijovic, C., Bain, S. C., Barnett, A. H., Vandewalle, C. L., Schuit, F., Gorus, F. K., Belgian Diabetes Registry, Tosi, R., Pozzilli, P., Todd, J. A. <strong>The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes.</strong> Hum. Molec. Genet. 5: 1075-1080, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8817351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8817351</a>] [<a href="https://doi.org/10.1093/hmg/5.7.1075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8817351">Nistico et al. (1996)</a> and <a href="#30" class="mim-tip-reference" title="Marron, M. P., Raffel, L. J., Garchon, H.-J., Jacob, C. O., Serrano-Rios, M., Martinez Larrad, M. T., Teng, W.-P., Park, Y., Zhang, Z.-X., Goldstein, D. R., Tao, Y.-W., Beaurain, G., Bach, J.-F., Huang, H.-S., Luo, D.-F., Zeidler, A., Rotter, J. I., Yang, M. C. K., Modilevsky, T., Maclaren, N. K., She, J.-X. <strong>Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups.</strong> Hum. Molec. Genet. 6: 1275-1282, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9259273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9259273</a>] [<a href="https://doi.org/10.1093/hmg/6.8.1275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9259273">Marron et al. (1997)</a> found increased transmission of the G allele of a 49A-G polymorphism (<a href="#0001">123890.0001</a>) in several populations with insulin-dependent diabetes mellitus that mapped to chromosome 2q33 (T1D12; <a href="/entry/601388">601388</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9259273+8817351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Lohmueller, K. E., Pearce, C. L., Pike, M., Lander, E. S., Hirschhorn, J. N. <strong>Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease.</strong> Nature Genet. 33: 177-182, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12524541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12524541</a>] [<a href="https://doi.org/10.1038/ng1071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12524541">Lohmueller et al. (2003)</a> performed a metaanalysis of 301 published studies of 25 different reported associations between genetic variants and common diseases. For 8 of the 25 associations, pooled analysis of follow-up studies yielded statistically significant replication of the first report, with modest estimated genetic effects. One of these 8 associations was that between CTLA4 and type 1 diabetes, as first reported by <a href="#32" class="mim-tip-reference" title="Nistico, L., Buzzetti, R., Pritchard, L. E., Van der Auwera, B., Giovannini, C., Bosi, E., Martinez Larrad, M. T., Serrano Rios, M., Chow, C. C., Cockram, C. S., Jacobs, K., Mijovic, C., Bain, S. C., Barnett, A. H., Vandewalle, C. L., Schuit, F., Gorus, F. K., Belgian Diabetes Registry, Tosi, R., Pozzilli, P., Todd, J. A. <strong>The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes.</strong> Hum. Molec. Genet. 5: 1075-1080, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8817351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8817351</a>] [<a href="https://doi.org/10.1093/hmg/5.7.1075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8817351">Nistico et al. (1996)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8817351+12524541" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Graves Disease</em></strong></p><p>
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<a href="#15" class="mim-tip-reference" title="Heward, J. M., Allahabadia, A., Armitage, M., Hattersley, A., Dodson, P. M., Macleod, K., Carr-Smith, J., Daykin, J., Daly, A., Sheppard, M. C., Holder, R. L., Barnett, A. H., Franklyn, J. A., Gough, S. C. L. <strong>The development of Graves' disease and the CTLA-4 gene on chromosome 2q33.</strong> J. Clin. Endocr. Metab. 84: 2398-2401, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10404810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10404810</a>] [<a href="https://doi.org/10.1210/jcem.84.7.5820" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10404810">Heward et al. (1999)</a> studied the A/G polymorphism of the CTLA4 gene in a case-control (743 individuals) and family-based (179 families) dataset of Caucasian subjects with Graves disease (<a href="/entry/275000">275000</a>). An increase in frequency of the G (alanine) allele was seen in patients with Graves disease compared with control subjects (42% vs 31.5%, respectively; corrected p less than 0.0002; odds ratio of 1.58). A significant difference in the distribution of GG, GA, and AA genotypes was observed between the groups (chi-square of 21.7; corrected P less than 0.00003). Increased transmission of the G allele was seen from heterozygous parents to affected offspring compared to unaffected offspring (chi-square of 5.7; p = 0.025). Circulating free T4 concentrations at diagnosis were significantly associated with CTLA4 genotype (F = 3.26; p of 0.04). These results supported the hypothesis that CTLA4 may play a role in regulating self-tolerance by the immune system and in the pathogenesis of autoimmune disorders such as Graves disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10404810" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Kouki, T., Sawai, Y., Gardine, C. A., Fisfalen, M.-E., Alegre, M.-L., DeGroot, L. J. <strong>CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves' disease.</strong> J. Immun. 165: 6606-6611, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11086105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11086105</a>] [<a href="https://doi.org/10.4049/jimmunol.165.11.6606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11086105">Kouki et al. (2000)</a> reported that there are more Graves disease patients with G/G or A/G alleles at nucleotide 49 of the CTLA4 gene and significantly fewer with the A/A allele compared with normal controls. Flow cytometric analysis failed to detect any differences in intracellular or surface expression of CTLA4 in Graves disease or Hashimoto thyroiditis patients compared with normal controls. T-cell proliferation in response to Epstein Barr virus-transformed B cells was significantly greater in subjects with the G/G allele than in those with the A/A allele. Incubation of anti-CTLA4 monoclonal antibody with peripheral blood mononuclear cells showed that individuals with the G/G allele had significantly less augmentation of the T-cell proliferative response than did individuals with the A/A allele. <a href="#22" class="mim-tip-reference" title="Kouki, T., Sawai, Y., Gardine, C. A., Fisfalen, M.-E., Alegre, M.-L., DeGroot, L. J. <strong>CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves' disease.</strong> J. Immun. 165: 6606-6611, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11086105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11086105</a>] [<a href="https://doi.org/10.4049/jimmunol.165.11.6606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11086105">Kouki et al. (2000)</a> concluded that the CTLA4 polymorphism affects the inhibitory function of the molecule and that the G allele is associated with reduced control of T-cell proliferation, thereby contributing to the pathogenesis of Graves disease and other autoimmune diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11086105" 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="#47" class="mim-tip-reference" title="Ueda, H., Howson, J. M. M., Esposito, L., Heward, J., Snook, H., Chamberlain, G., Rainbow, D. B., Hunter, K. M. D., Smith, A. N., DiGenova, G., Herr, M. H., Dahlman, I., and 41 others. <strong>Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease.</strong> Nature 423: 506-511, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12724780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12724780</a>] [<a href="https://doi.org/10.1038/nature01621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12724780">Ueda et al. (2003)</a> did not find an association between the 49A-G polymorphism and Graves disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12724780" 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>Smoking and demographic variables are known to be risk factors for the development of thyroid-associated orbitopathy (TAO) among patients with Graves hyperthyroidism. <a href="#48" class="mim-tip-reference" title="Vaidya, B., Imrie, H., Perros, P., Dickinson, J., McCarthy, M. I., Kendall-Taylor, P., Pearce, S. H. S. <strong>Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism confers susceptibility to thyroid associated orbitopathy.</strong> Lancet 354: 743-744, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10475192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10475192</a>] [<a href="https://doi.org/10.1016/S0140-6736(99)01465-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10475192">Vaidya et al. (1999)</a> showed that the presence and severity of TAO are associated with a specific allele of the CTLA4 gene. In addition to the demonstrated linkage and association of the CTLA4 locus with both type I diabetes (T1D12; <a href="/entry/601388">601388</a>) and Graves disease, <a href="#48" class="mim-tip-reference" title="Vaidya, B., Imrie, H., Perros, P., Dickinson, J., McCarthy, M. I., Kendall-Taylor, P., Pearce, S. H. S. <strong>Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism confers susceptibility to thyroid associated orbitopathy.</strong> Lancet 354: 743-744, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10475192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10475192</a>] [<a href="https://doi.org/10.1016/S0140-6736(99)01465-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10475192">Vaidya et al. (1999)</a> presented evidence that the biallelic polymorphism (A/G) at codon 17 of the CTLA4 gene also conferred susceptibility to TAO. They showed that the G-carrying genotypes of CTLA4 (AG and GG) were associated with an increased risk of TAO, and that this was independent of sex, smoking status, or previous radioiodine administration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10475192" 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="#53" class="mim-tip-reference" title="Wang, P.-W., Liu, R.-T., Juo, S.-H. H., Wang, S.-T., Hu, Y.-H., Hsieh, C.-J., Chen, M.-H., Chen, I.-Y., Wu, C.-L. <strong>Cytotoxic T lymphocyte-associated molecule-4 polymorphism and relapse of Graves' hyperthyroidism after antithyroid withdrawal.</strong> J. Clin. Endocr. Metab. 89: 169-173, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14715845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14715845</a>] [<a href="https://doi.org/10.1210/jc.2003-030854" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14715845">Wang et al. (2004)</a> showed an association between the 49G allele and early relapse of Graves disease following discontinuation of drug treatment. In a follow-up study of an additional 60 patients with GRD, <a href="#52" class="mim-tip-reference" title="Wang, P.-W., Chen, I.-Y., Liu, R.-T., Hsieh, C.-J., Hsi, E., Juo, S.-H. H. <strong>Cytotoxic T lymphocyte-associated molecule-4 gene polymorphism and hyperthyroid Graves' disease relapse after antithyroid drug withdrawal: a follow-up study.</strong> J. Clin. Endocr. Metab. 92: 2513-2518, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17426089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17426089</a>] [<a href="https://doi.org/10.1210/jc.2006-2761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17426089">Wang et al. (2007)</a> found by multivariate logistic regression analysis that the GG genotype had an adjusted odds ratio of 2.2 (95% CI, 1.1-4.4) compared with the combined group of GA plus AA. Other significant predictors of relapse were large goiter size at the end of treatment and positive TSH-binding inhibitory Ig at the end of treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17426089+14715845" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The production of high titers of autoantibodies against thyroglobulin (<a href="/entry/188450">188450</a>) and thyroid peroxidase (<a href="/entry/606765">606765</a>) is a hallmark of autoimmune thyroid diseases. To identify susceptibility genes for the production of thyroid antibodies, <a href="#46" class="mim-tip-reference" title="Tomer, Y., Greenberg, D. A., Barbesino, G., Concepcion, E., Davies, T. F. <strong>CTLA-4 and not CD28 is a susceptibility gene for thyroid autoantibody production.</strong> J. Clin. Endocr. Metab. 86: 1687-1693, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11297604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11297604</a>] [<a href="https://doi.org/10.1210/jcem.86.4.7372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11297604">Tomer et al. (2001)</a> performed a genomewide scan in 56 multiplex families (323 individuals) in which all family members with autoimmune thyroid diseases and/or detectable thyroid antibodies were considered affected. The highest 2-point lod score of 3.6 was obtained for marker D2S325 on chromosome 2q33 at 210.9 cM. This locus showed no evidence for linkage to Graves disease or Hashimoto thyroiditis (2-point lod scores, 0.42 for Graves disease and -0.60 for Hashimoto thyroiditis), demonstrating that the gene in this region conferred susceptibility to thyroid antibodies, but that clinical disease development required additional genetic and/or environmental factors. Multipoint linkage analysis for thyroid antibodies using additional markers yielded a maximum lod score of 4.2 for marker D2S155 at 209.8 cM (with heterogeneity, alpha = 0.41). There was a significantly increased frequency of the 49G allele in probands of the linked families compared with probands of the unlinked families or with controls. <a href="#46" class="mim-tip-reference" title="Tomer, Y., Greenberg, D. A., Barbesino, G., Concepcion, E., Davies, T. F. <strong>CTLA-4 and not CD28 is a susceptibility gene for thyroid autoantibody production.</strong> J. Clin. Endocr. Metab. 86: 1687-1693, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11297604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11297604</a>] [<a href="https://doi.org/10.1210/jcem.86.4.7372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11297604">Tomer et al. (2001)</a> concluded that the major gene for thyroid antibody production on chromosome 2q33 was the CTLA4 gene, which contributed to the genetic susceptibility to thyroid antibody production, but that there was no evidence that it contributed specifically to Graves or Hashimoto diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11297604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To investigate an association between the 49A/G polymorphism of the CTLA4 gene and remission of Graves disease during antithyroid drug treatment, <a href="#21" class="mim-tip-reference" title="Kinjo, Y., Takasu, N., Komiya, I., Tomoyose, T., Takara, M., Kouki, T., Shimajiri, Y., Yabiku, K., Yoshimura, H. <strong>Remission of Graves' hyperthyroidism and A/G polymorphism at position 49 in exon 1 of cytotoxic T lymphocyte-associated molecule-4 gene.</strong> J. Clin. Endocr. Metab. 87: 2593-2596, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050220</a>] [<a href="https://doi.org/10.1210/jcem.87.6.8612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12050220">Kinjo et al. (2002)</a> studied this polymorphism in 144 Japanese Graves disease patients treated with antithyroid drugs. A significant increase in the frequency of the G allele was seen in patients compared with controls (p = 0.0095). The patients were divided into 3 groups according to time of disappearance of TSH receptor antibody (TRAb) after the start of treatment. In group A patients, TRAb had disappeared within 1 year after the start of treatment; in group B, TRAb had disappeared between the beginning of the second year and the end of the fifth year of treatment; and in group C, TRAb continued to be positive after 5 years of treatment. The frequencies of the GG genotype and the G allele were significantly higher in group C patients with persistently positive TRAb over 5 years of treatment than in the other groups (p less than 0.0001). Group C patients did not have the AA genotype. The periods of time until remission were significantly shorter in the AA genotype. The authors concluded that Graves disease patients with the G allele need to continue antithyroid drug treatment for longer periods. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050220" 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="#53" class="mim-tip-reference" title="Wang, P.-W., Liu, R.-T., Juo, S.-H. H., Wang, S.-T., Hu, Y.-H., Hsieh, C.-J., Chen, M.-H., Chen, I.-Y., Wu, C.-L. <strong>Cytotoxic T lymphocyte-associated molecule-4 polymorphism and relapse of Graves' hyperthyroidism after antithyroid withdrawal.</strong> J. Clin. Endocr. Metab. 89: 169-173, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14715845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14715845</a>] [<a href="https://doi.org/10.1210/jc.2003-030854" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14715845">Wang et al. (2004)</a> tested whether the G allele of the 49A/G SNP in the CTLA4 gene, associated with higher risk of developing Graves disease, was associated with early relapse of the disease after drug withdrawal in 148 Chinese patients with Graves disease and 171 controls. The G/G genotype had a 79% frequency in patients who experienced relapse within 9 months compared to 39% in patients who relapsed 3 or more years after discontinuation of treatment. At the end of treatment, the percentage of patients with persistent TSH receptor (TSHR; <a href="/entry/603372">603372</a>) antibody was statistically different (A/A, 9.0%; A/G, 20.8%; G/G, 45.5%; p = 0.004). The authors concluded that the A/G polymorphism of the CTLA4 gene affects the progress of GD and that the G/G genotype is associated with poor outcome. They also noted that patients with the G/G genotype may not be candidates for antithyroid drugs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14715845" 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="Kavvoura, F. K., Akamizu, T., Awata, T., Ban, Y., Chistiakov, D. A., Frydecka, I., Ghaderi, A., Gough, S. C., Hiromatsu, Y., Ploski, R., Wang, P.-W., Ban, Y., and 16 others. <strong>Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: a meta-analysis.</strong> J. Clin. Endocr. Metab. 92: 3162-3170, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17504905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17504905</a>] [<a href="https://doi.org/10.1210/jc.2007-0147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17504905">Kavvoura et al. (2007)</a> performed a metaanalysis examining the association of the CTLA4 49A-G and CT60 polymorphisms with increased susceptibility to Graves disease (GRD; see <a href="/entry/275000">275000</a>) and/or Hashimoto thyroiditis (HT; see <a href="/entry/140300">140300</a>), which included group-level data from more than 13,000 subjects and individual-level data from more than 5,000 subjects. The group-level data showed highly significant associations of both GRD and HT with each polymorphism separately, with p values in the range of 10(-3) and 10(-16) in the main analysis. The individual-level data allowed the consideration of haplotypes, including both polymorphisms. <a href="#20" class="mim-tip-reference" title="Kavvoura, F. K., Akamizu, T., Awata, T., Ban, Y., Chistiakov, D. A., Frydecka, I., Ghaderi, A., Gough, S. C., Hiromatsu, Y., Ploski, R., Wang, P.-W., Ban, Y., and 16 others. <strong>Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: a meta-analysis.</strong> J. Clin. Endocr. Metab. 92: 3162-3170, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17504905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17504905</a>] [<a href="https://doi.org/10.1210/jc.2007-0147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17504905">Kavvoura et al. (2007)</a> found that the association with the 49A-G polymorphism was probably mostly the result of linkage disequilibrium with CT60. The G allele of the CT60 polymorphism increased the odds of both GRD and HT by 1.4-fold. A dose-effect association was also demonstrated, as the presence of 2 copies of the susceptible haplotype GG almost doubled the odds compared with 1 copy of GG. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17504905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Chu, X., Pan, C.-M., Zhao, S.-X., Liang, J., Gao, G.-Q., Zhang, X.-M., Yuan, G.-Y., Li, C.-G., Xue, L.-Q., Shen, M., Liu, W., Xie, F., and 37 others. <strong>A genome-wide association study identifies two new risk loci for Graves' disease.</strong> Nature Genet. 43: 897-901, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21841780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21841780</a>] [<a href="https://doi.org/10.1038/ng.898" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21841780">Chu et al. (2011)</a> conducted a genomewide association study in 1,536 individuals with Graves disease and 1,516 controls, and then evaluated a group of associated SNPs in a second set of 3,994 cases and 3,510 controls. <a href="#7" class="mim-tip-reference" title="Chu, X., Pan, C.-M., Zhao, S.-X., Liang, J., Gao, G.-Q., Zhang, X.-M., Yuan, G.-Y., Li, C.-G., Xue, L.-Q., Shen, M., Liu, W., Xie, F., and 37 others. <strong>A genome-wide association study identifies two new risk loci for Graves' disease.</strong> Nature Genet. 43: 897-901, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21841780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21841780</a>] [<a href="https://doi.org/10.1038/ng.898" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21841780">Chu et al. (2011)</a> confirmed the association with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1024161;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1024161</a> at CTLA4; T is the risk allele (combined odds ratio = 1.30; 95% CI 1.23-1.38; p = 2.34 x 10(-17)). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21841780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Other Endocrine Autoimmune Diseases</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Donner, H., Braun, J., Seidl, C., Rau, H., Finke, R., Ventz, M., Walfish, P. G., Usadel, K. H., Badenhoop, K. <strong>Codon 17 polymorphism of the cytotoxic T lymphocyte antigen 4 gene in Hashimoto's thyroiditis and Addison's disease.</strong> J. Clin. Endocr. Metab. 82: 4130-4132, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398726</a>] [<a href="https://doi.org/10.1210/jcem.82.12.4406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9398726">Donner et al. (1997)</a> found an association between Hashimoto thyroiditis (<a href="/entry/140300">140300</a>) and the 49G allele. Although patients with Addison disease (<a href="/entry/240200">240200</a>) did not differ significantly from controls with regard to the 49G-A polymorphism, those patients carrying the susceptibility marker, human leukocyte antigen DQA1*0501, had a significantly higher frequency of the G allele compared to controls with the same DQA1 allele (P less than 0.05). <a href="#10" class="mim-tip-reference" title="Donner, H., Braun, J., Seidl, C., Rau, H., Finke, R., Ventz, M., Walfish, P. G., Usadel, K. H., Badenhoop, K. <strong>Codon 17 polymorphism of the cytotoxic T lymphocyte antigen 4 gene in Hashimoto's thyroiditis and Addison's disease.</strong> J. Clin. Endocr. Metab. 82: 4130-4132, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398726</a>] [<a href="https://doi.org/10.1210/jcem.82.12.4406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9398726">Donner et al. (1997)</a> concluded that the 49G (ala17) allele of the CTLA4 gene confers genetic susceptibility to Hashimoto thyroiditis and to Addison disease in individuals who also carry DQA1*0501+. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9398726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Celiac Disease</em></strong></p><p>
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<a href="#9" class="mim-tip-reference" title="Djilali-Saiah, I., Schmitz, J., Harfouch-Hammoud, E., Mougenot, J.-F., Bach, J.-F., Caillat-Zucman, S. <strong>CTLA-4 gene polymorphism is associated with predisposition to coeliac disease.</strong> Gut 43: 187-189, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10189842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10189842</a>] [<a href="https://doi.org/10.1136/gut.43.2.187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10189842">Djilali-Saiah et al. (1998)</a> found a significantly increased frequency of the 49A allele in 101 French Caucasian patients with celiac disease (CELIAC3; <a href="/entry/609755">609755</a>) compared to controls (82.2% vs 65.8%, p less than 0.0001), reflecting the increased frequency of A/A homozygotes among patients compared with controls (68.3% vs 47.7%, p = 0.002). The effect remained after stratification of patients according to their DR-DQ phenotype. The authors concluded that the A allele of the CTLA4 position 49 polymorphism conferred an HLA-independent predisposition to celiac disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10189842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Naluai, A. T., Nilsson, S., Samuelsson, L., Gudjonsdottir, A. H., Ascher, H., Ek, J., Hallberg, B., Kristiansson, B., Martinsson, T., Nerman, O., Sollid, L. M., Wahlstrom, J. <strong>The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory diseases.</strong> Tissue Antigens 56: 350-355, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11098935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11098935</a>] [<a href="https://doi.org/10.1034/j.1399-0039.2000.560407.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11098935">Naluai et al. (2000)</a> analyzed the 49A/G polymorphism (<a href="#0001">123890.0001</a>) in 107 Swedish and Norwegian families with celiac disease and found a significant association, with preferential transmission of the 49A allele by the transmission disequilibrium test (p less than 0.007). Nonparametric linkage analysis yielded a score of 2.1 (p = 0.018), suggesting that the CTLA4 region is a susceptibility region in celiac disease. <a href="#31" class="mim-tip-reference" title="Naluai, A. T., Nilsson, S., Samuelsson, L., Gudjonsdottir, A. H., Ascher, H., Ek, J., Hallberg, B., Kristiansson, B., Martinsson, T., Nerman, O., Sollid, L. M., Wahlstrom, J. <strong>The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory diseases.</strong> Tissue Antigens 56: 350-355, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11098935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11098935</a>] [<a href="https://doi.org/10.1034/j.1399-0039.2000.560407.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11098935">Naluai et al. (2000)</a> noted that, of several chronic inflammatory diseases exhibiting associations to the CTLA4 49A/G polymorphism, celiac disease is the only one associated with the A allele, suggesting that the 49A/G alleles of CTLA4 are in linkage disequilibrium with 2 distinct disease-predisposing alleles with separate effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11098935" 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="#49" class="mim-tip-reference" title="van Belzen, M. J., Mulder, C. J. J., Zhernakova, A., Pearson, P. L., Houwen, R. H. J., Wijmenga, C. <strong>CTLA4 +49A/G and CT60 polymorphisms in Dutch coeliac disease patients.</strong> Europ. J. Hum. Genet. 12: 782-785, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15199380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15199380</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15199380">Van Belzen et al. (2004)</a> genotyped 215 Dutch celiac patients and 213 controls for the 49A-G and CT60 (<a href="#0002">123890.0002</a>) polymorphisms in the CTLA4 gene. They found no significant difference between patients and controls in the frequency of the 49G allele, but did find an increase in the frequency of the CT60 G allele in patients (p = 0.048). <a href="#49" class="mim-tip-reference" title="van Belzen, M. J., Mulder, C. J. J., Zhernakova, A., Pearson, P. L., Houwen, R. H. J., Wijmenga, C. <strong>CTLA4 +49A/G and CT60 polymorphisms in Dutch coeliac disease patients.</strong> Europ. J. Hum. Genet. 12: 782-785, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15199380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15199380</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15199380">Van Belzen et al. (2004)</a> concluded that CTLA4 is involved in the development of celiac disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15199380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Hunt, K. A., McGovern, D. P. B., Kumar, P. J., Ghosh, S., Travis, S. P. L., Walters, J. R. F., Jewell, D. P., Playford, R. J., van Heel, D. A. <strong>A common CTLA4 haplotype associated with coeliac disease.</strong> Europ. J. Hum. Genet. 13: 440-444, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15657618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15657618</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15657618">Hunt et al. (2005)</a> pointed out that 5 linkage studies had individually provided nominally significant evidence for a celiac disease susceptibility locus on chromosome 2q (2q33), making CTLA4 a promising candidate gene. They genotyped CTLA4 variants to tag all common haplotypes (more than 5% frequency) and a variant of inducible costimulator (ICOS; <a href="/entry/604558">604558</a>), which also maps to 2q33, in 340 white U.K. celiac disease cases and in a group of healthy controls. A common CTLA4 haplotype showed strong association with celiac disease and contained multiple alleles reported to affect immunologic function. <a href="#18" class="mim-tip-reference" title="Hunt, K. A., McGovern, D. P. B., Kumar, P. J., Ghosh, S., Travis, S. P. L., Walters, J. R. F., Jewell, D. P., Playford, R. J., van Heel, D. A. <strong>A common CTLA4 haplotype associated with coeliac disease.</strong> Europ. J. Hum. Genet. 13: 440-444, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15657618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15657618</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15657618">Hunt et al. (2005)</a> suggested that loss of tolerance to dietary antigens in celiac disease may be mediated in part by heritable variants in cosignaling genes regulating T-cell responses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15657618" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Systemic Lupus Erythematosus</em></strong></p><p>
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<a href="#17" class="mim-tip-reference" title="Hudson, L. L., Rocca, K., Song, Y. W., Pandey, J. P. <strong>CTLA-4 gene polymorphisms in systemic lupus erythematosus: a highly significant association with a determinant in the promoter region.</strong> Hum. Genet. 111: 452-455, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12384790/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12384790</a>] [<a href="https://doi.org/10.1007/s00439-002-0807-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12384790">Hudson et al. (2002)</a> investigated association between systemic lupus erythematosus (SLE; <a href="/entry/152700">152700</a>) and SNPs of the CTLA4 gene. The genotypes at position -1722(T/C) were significantly associated with SLE. The frequency of T/T homozygotes was higher in patients than in controls; conversely, the frequency of C/C homozygotes and C/T heterozygotes were higher in controls than in patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12384790" 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 metaanalysis of 7 published studies and their own study, <a href="#3" class="mim-tip-reference" title="Barreto, M., Santos, E., Ferreira, R., Fesel, C., Fontes, M. F., Pereira, C., Martins, B., Andreia, R., Viana, J. F., Crespo, F., Vasconcelos, C., Ferreira, C., Vicente, A. M. <strong>Evidence for CTLA4 as a susceptibility gene for systemic lupus erythematosus.</strong> Europ. J. Hum. Genet. 12: 620-626, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15138458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15138458</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201214" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15138458">Barreto et al. (2004)</a> examined the association between the 49A-G SNP in exon 1 of the CTLA4 gene and SLE. The authors found that individuals with the GG genotype were at significantly higher risk of developing SLE; carriers of the A allele had a significantly lower risk of developing the disease, and the AA genotype acted as a protective genotype for SLE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15138458" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Hepatitis B Virus Clearance and Persistence</em></strong></p><p>
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<a href="#45" class="mim-tip-reference" title="Thio, C. L., Mosbruger, T. L., Kaslow, R. A., Karp, C. L., Strathdee, S. A., Vlahov, D., O'Brien, S. J., Astemborski, J., Thomas, D. L. <strong>Cytotoxic T-lymphocyte antigen 4 gene and recovery from hepatitis B virus infection.</strong> J. Virol. 78: 11258-11262, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15452244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15452244</a>] [<a href="https://doi.org/10.1128/JVI.78.20.11258-11262.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15452244">Thio et al. (2004)</a> genotyped 6 SNPs in CTLA4 in a large cohort of individuals with either hepatitis B virus (HBV; see <a href="/entry/610424">610424</a>) clearance or persistence. They found that the wildtype haplotype, which contains -1722T and +49A, was associated with viral persistence. In contrast, haplotypes containing +49G either alone or with -1722C were associated with viral clearance. The association with viral clearance was stronger for individuals homozygous for +49G. <a href="#45" class="mim-tip-reference" title="Thio, C. L., Mosbruger, T. L., Kaslow, R. A., Karp, C. L., Strathdee, S. A., Vlahov, D., O'Brien, S. J., Astemborski, J., Thomas, D. L. <strong>Cytotoxic T-lymphocyte antigen 4 gene and recovery from hepatitis B virus infection.</strong> J. Virol. 78: 11258-11262, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15452244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15452244</a>] [<a href="https://doi.org/10.1128/JVI.78.20.11258-11262.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15452244">Thio et al. (2004)</a> concluded that genes important in immune system counterregulation are also important in recovery from chronic viral illness. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15452244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Immune Dysregulation with Autoimmunity, Immunodeficiency, and Lymphoproliferation</em></strong></p><p>
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In 6 patients from 4 families with immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL; <a href="/entry/616100">616100</a>), <a href="#23" class="mim-tip-reference" title="Kuehn, H. S., Ouyang W., Lo, B., Deenick, E. K., Niemela, J. E., Avery, D. T., Schickel, J.-N., Tran, D. Q., Stoddard, J., Zhang, Y., Frucht, D. M., Dumitriu, B., and 24 others. <strong>Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.</strong> Science 345: 1623-1627, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25213377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25213377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25213377[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1255904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25213377">Kuehn et al. (2014)</a> identified 4 different heterozygous loss-of-function mutations in the CTLA4 gene (see, e.g., <a href="#0003">123890.0003</a>-<a href="#0005">123890.0005</a>). Patients had decreased numbers of circulating naive CD45RA+ T cells compared to controls, as well as progressive loss of circulating B cells. Patient regulatory T cells showed decreased FOXP3 (<a href="/entry/300292">300292</a>) and IL2RA (<a href="/entry/147730">147730</a>) expression, and these cells poorly suppressed the proliferation of cocultured T responder cells in vitro. Knockdown of CTLA4 using siRNA in control mononuclear cells recapitulated the hyperproliferative T-cell phenotype. Patients had increased frequency of autoreactive CD21(lo) B cells, which are considered anergic or exhausted, and these cells showed increased tendency for apoptosis as well as decreased ability to secrete immunoglobulin. These changes resulted in B-cell lymphopenia and were believed to be a result of regulatory T-cell dysfunction. The findings demonstrated that full expression of CTLA4 is required to govern T- and B-cell lymphocyte homeostasis, and that reduction of CTLA4 expression contributes to loss of immune tolerance and causes infiltrative autoimmune disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25213377" 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 11 patients from 6 unrelated families with IDAIL, <a href="#41" class="mim-tip-reference" title="Schubert, D., Bode, C., Kenefeck, R., Hou, T. Z., Wing, J. B., Kennedy, A., Bulashevska, A., Petersen, B.-S., Schaffer, A. A., Gruning, B. A., Unger, S., Frede, N., and 28 others. <strong>Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.</strong> Nature Med. 20: 1410-1416, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25329329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25329329</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25329329[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.3746" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25329329">Schubert et al. (2014)</a> identified 6 different heterozygous mutations in the CTLA4 gene (see, e.g., <a href="#0006">123890.0006</a>-<a href="#0008">123890.0008</a>). The mutation in the first family was found by whole-exome sequencing; mutations in subsequent families were found by direct screening of the CTLA4 gene in 71 unrelated probands with common variable immunodeficiency (CVID) and enteropathy or autoimmunity. Patient regulatory T cells showed decreased CTLA4 protein expression. In vitro studies showed impaired suppressive function of regulatory T cells and impaired ligand capture and transendocytosis of CD80 (<a href="/entry/112203">112203</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25329329" 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>CTLA4 has a role in T-cell activation and shares significant sequence identity with CD28; the 2 mouse proteins are 76% alike. Whereas CD28 is found on the membrane of resting T cells, CTLA4 is detectable only on cells activated after antigen presentation. Both molecules bind to the same ligands. <a href="#54" class="mim-tip-reference" title="Waterhouse, P., Penninger, J. M., Timms, E., Wakeham, A., Shahinian, A., Lee, K. P., Thompson, C. B., Griesser, H., Mak, T. W. <strong>Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4.</strong> Science 270: 985-988, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7481803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7481803</a>] [<a href="https://doi.org/10.1126/science.270.5238.985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7481803">Waterhouse et al. (1995)</a> showed that homozygous Ctla4 gene-targeted mice accumulated T-cell blasts in their lymph nodes and spleens, which were enlarged 5 to 10 times normal. In contrast, CD28-homozygous knockout mice had diminished T-cell responses (<a href="#43" class="mim-tip-reference" title="Shahinian, A., Pfeffer, K., Lee, K. P., Kundig, T. M., Kishihara, K., Wakeham, A., Kawai, K., Ohashi, P. S., Thompson, C. B., Mak, T. W. <strong>Differential T cell costimulatory requirements in CD28-deficient mice.</strong> Science 261: 609-612, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7688139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7688139</a>] [<a href="https://doi.org/10.1126/science.7688139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7688139">Shahinian et al., 1993</a>). <a href="#54" class="mim-tip-reference" title="Waterhouse, P., Penninger, J. M., Timms, E., Wakeham, A., Shahinian, A., Lee, K. P., Thompson, C. B., Griesser, H., Mak, T. W. <strong>Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4.</strong> Science 270: 985-988, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7481803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7481803</a>] [<a href="https://doi.org/10.1126/science.270.5238.985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7481803">Waterhouse et al. (1995)</a> found that Ctla4-deficient mice had much higher serum immunoglobin concentrations than normal, that their B cells exhibited activation markers, and that many of their tissues showed extensive lymphocyte proliferation. The Ctla4-knockout mice became moribund by 3 to 4 weeks of age and died of apparent myocardial failure due to lymphocytic infiltration. Although CTLA4-deficient T cells proliferated spontaneously and strongly when stimulated through the T-cell receptor, they were sensitive to cell death induced by cross-linking of the Fas receptor and by gamma irradiation. Through these and other findings, the authors concluded that CTLA4 plays an important inhibitory role in regulating lymphocyte expansion. <a href="#2" class="mim-tip-reference" title="Allison, J. P., Krummel, M. F. <strong>The yin and yang of T cell costimulation.</strong> Science 270: 932-933, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7481795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7481795</a>] [<a href="https://doi.org/10.1126/science.270.5238.932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7481795">Allison and Krummel (1995)</a> reviewed the current literature on T-cell costimulation in light of the findings by <a href="#54" class="mim-tip-reference" title="Waterhouse, P., Penninger, J. M., Timms, E., Wakeham, A., Shahinian, A., Lee, K. P., Thompson, C. B., Griesser, H., Mak, T. W. <strong>Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4.</strong> Science 270: 985-988, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7481803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7481803</a>] [<a href="https://doi.org/10.1126/science.270.5238.985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7481803">Waterhouse et al. (1995)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7688139+7481795+7481803" 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>Mice deficient in either Jak3 (<a href="/entry/600173">600173</a>) or Ctla4 have similar predominantly CD4-positive peripheral T-cell phenotypes, but die from SCID and lymphoproliferative disorder, respectively. <a href="#12" class="mim-tip-reference" title="Gozalo-Sanmillan, S., McNally, J. M., Lin, M. Y., Chambers, C. A., Berg, L. J. <strong>Cutting edge: two distinct mechanisms lead to impaired T cell homeostasis in Janus kinase 3- and CTLA-4-deficient mice.</strong> J. Immun. 166: 727-730, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11145642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11145642</a>] [<a href="https://doi.org/10.4049/jimmunol.166.2.727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11145642">Gozalo-Sanmillan et al. (2001)</a> used CDR3 spectratyping analysis of T-cell receptor repertoires of Jak3- and Ctla4-deficient mice. Ctla4 -/- mice had the same diverse repertoire as control unimmunized mice, whereas Jak3 -/- peripheral but not thymic T cells had a limited number of expanded T-cell clones, suggesting an antigen-dependent activation in the Jak3-deficient mice as opposed to a universal activation in the Ctla4-deficient mice. The authors concluded that the 2 similar phenotypes of T-cell expansion are derived by distinct mechanisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11145642" 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="Bour-Jordan, H., Grogan, J. L., Tang, Q., Auger, J. A., Locksley, R. M., Bluestone, J. A. <strong>CTLA-4 regulates the requirement for cytokine-induced signals in T(H)2 lineage commitment.</strong> Nature Immun. 4: 182-188, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12524538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12524538</a>] [<a href="https://doi.org/10.1038/ni884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12524538">Bour-Jordan et al. (2003)</a> showed that T cells from double-knockout mice deficient in Ctla4 and Stat6 (<a href="/entry/601512">601512</a>) were skewed toward a Th2 phenotype in vitro and in vivo by bypassing the need for Stat6. Instead, induction of Gata3 (<a href="/entry/131320">131320</a>) occurred in vitro and Cd4-positive cells migrated to peripheral tissues in vivo. In addition, T-cell receptor crosslinking induced a relative increase of Nfatc1 (<a href="/entry/600489">600489</a>) versus Nfatc2 (<a href="/entry/600490">600490</a>) nuclear translocation and enhanced NFKB (<a href="/entry/164011">164011</a>) activation compared with Stat6 -/- T cells. <a href="#4" class="mim-tip-reference" title="Bour-Jordan, H., Grogan, J. L., Tang, Q., Auger, J. A., Locksley, R. M., Bluestone, J. A. <strong>CTLA-4 regulates the requirement for cytokine-induced signals in T(H)2 lineage commitment.</strong> Nature Immun. 4: 182-188, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12524538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12524538</a>] [<a href="https://doi.org/10.1038/ni884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12524538">Bour-Jordan et al. (2003)</a> proposed that CTLA4 regulates T-cell differentiation by controlling the overall strength of the T-cell activation signal, bypassing the cytokine dependency of Th2 differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12524538" 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="#55" class="mim-tip-reference" title="Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T., Sakaguchi, S. <strong>CTLA-4 control over Foxp3+ regulatory T cell function.</strong> Science 322: 271-275, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18845758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18845758</a>] [<a href="https://doi.org/10.1126/science.1160062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18845758">Wing et al. (2008)</a> found that conditional deletion of Ctla4 in Foxp3 (<a href="/entry/300292">300292</a>)-positive Tregs resulted in spontaneous development of systemic lymphoproliferation, fatal T cell-mediated autoimmune disease, and hyper-IgE production in mice 7 weeks after birth. Reconstitution of mice with Ctla4 -/- Tregs halted tumor growth and enhanced survival. Flow cytometric analysis showed no alteration in thymic selection of Tregs, but there was a change in expression of Cd80 (<a href="/entry/112203">112203</a>) and Cd86 (<a href="/entry/601020">601020</a>) in peripheral DCs. <a href="#55" class="mim-tip-reference" title="Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T., Sakaguchi, S. <strong>CTLA-4 control over Foxp3+ regulatory T cell function.</strong> Science 322: 271-275, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18845758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18845758</a>] [<a href="https://doi.org/10.1126/science.1160062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18845758">Wing et al. (2008)</a> proposed that natural Tregs may require CTLA4 to suppress immune responses by affecting the potency of APCs to activate other T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18845758" 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="#51" class="mim-tip-reference" title="vom Berg, J., Vrohlings, M., Haller, S., Haimovici, A., Kulig, P., Sledzinska, A., Weller, M., Becher, B. <strong>Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection.</strong> J. Exp. Med. 210: 2803-2811, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24277150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24277150</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24277150[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20130678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24277150">Vom Berg et al. (2013)</a> used a syngeneic mouse model for glioblastoma (GB; see <a href="/entry/137800">137800</a>) and administered cytokines in the tumor area to overcome the immunosuppressive GB microenvironment. The authors found that Il12 (see <a href="/entry/161561">161561</a>), but not Il23 (see <a href="/entry/605580">605580</a>), reversed GB-induced immunosuppression and led to tumor clearance in a T cell-dependent manner. To better replicate the human clinical situation, <a href="#51" class="mim-tip-reference" title="vom Berg, J., Vrohlings, M., Haller, S., Haimovici, A., Kulig, P., Sledzinska, A., Weller, M., Becher, B. <strong>Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection.</strong> J. Exp. Med. 210: 2803-2811, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24277150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24277150</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24277150[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20130678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24277150">vom Berg et al. (2013)</a> delayed therapy until after GB progression. They found that intratumoral application of Il12 combined with systemic anti-Ctla4, but not monotherapy with either Il12 or anti-Ctla4, led to tumor eradication even at advanced disease stages. The Il12 and anti-Ctla4 combination treatment acted predominantly on Cd4-positive T cells, causing a drastic reduction in Foxp3-positive Tregs and an increase in effector T cells. <a href="#51" class="mim-tip-reference" title="vom Berg, J., Vrohlings, M., Haller, S., Haimovici, A., Kulig, P., Sledzinska, A., Weller, M., Becher, B. <strong>Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection.</strong> J. Exp. Med. 210: 2803-2811, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24277150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24277150</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24277150[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20130678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24277150">Vom Berg et al. (2013)</a> proposed that the combination of intratumoral IL12 and anti-CTLA4 should be tested in clinical trials for treatment of GB and, possibly, other solid tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24277150" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs231775 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs231775;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/rs231775?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=rs231775" 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=rs231775" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#32" class="mim-tip-reference" title="Nistico, L., Buzzetti, R., Pritchard, L. E., Van der Auwera, B., Giovannini, C., Bosi, E., Martinez Larrad, M. T., Serrano Rios, M., Chow, C. C., Cockram, C. S., Jacobs, K., Mijovic, C., Bain, S. C., Barnett, A. H., Vandewalle, C. L., Schuit, F., Gorus, F. K., Belgian Diabetes Registry, Tosi, R., Pozzilli, P., Todd, J. A. <strong>The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes.</strong> Hum. Molec. Genet. 5: 1075-1080, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8817351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8817351</a>] [<a href="https://doi.org/10.1093/hmg/5.7.1075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8817351">Nistico et al. (1996)</a> identified a 49A-G transition polymorphism in exon 1 of the CTLA4 gene, resulting in a thr17-to-ala (T17A) substitution. Among 529 Belgian control individuals, the frequencies for the 49A and 49G alleles were 68% and 32%, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8817351" 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 48 Italian families in which at least 2 sibs were affected with type 1 diabetes mellitus (T1D12; <a href="/entry/601388">601388</a>), <a href="#32" class="mim-tip-reference" title="Nistico, L., Buzzetti, R., Pritchard, L. E., Van der Auwera, B., Giovannini, C., Bosi, E., Martinez Larrad, M. T., Serrano Rios, M., Chow, C. C., Cockram, C. S., Jacobs, K., Mijovic, C., Bain, S. C., Barnett, A. H., Vandewalle, C. L., Schuit, F., Gorus, F. K., Belgian Diabetes Registry, Tosi, R., Pozzilli, P., Todd, J. A. <strong>The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes.</strong> Hum. Molec. Genet. 5: 1075-1080, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8817351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8817351</a>] [<a href="https://doi.org/10.1093/hmg/5.7.1075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8817351">Nistico et al. (1996)</a> found evidence for preferential transmission of the 49G allele to affected offspring. Similar findings were obtained for 44 Spanish IDDM families, but not for families from the United Kingdom, Sardinia, or the US. <a href="#30" class="mim-tip-reference" title="Marron, M. P., Raffel, L. J., Garchon, H.-J., Jacob, C. O., Serrano-Rios, M., Martinez Larrad, M. T., Teng, W.-P., Park, Y., Zhang, Z.-X., Goldstein, D. R., Tao, Y.-W., Beaurain, G., Bach, J.-F., Huang, H.-S., Luo, D.-F., Zeidler, A., Rotter, J. I., Yang, M. C. K., Modilevsky, T., Maclaren, N. K., She, J.-X. <strong>Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups.</strong> Hum. Molec. Genet. 6: 1275-1282, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9259273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9259273</a>] [<a href="https://doi.org/10.1093/hmg/6.8.1275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9259273">Marron et al. (1997)</a> found highly significant transmission of the 49G allele in patients with IDDM in 3 Mediterranean European populations (Italian, Spanish, and French), a Mexican American population, and Korean population. However, significant heterogeneity was observed; datasets of British, Sardinian, and Chinese populations did not show any deviation for the A/G polymorphism, whereas the Caucasian American dataset showed a weak transmission deviation. The results suggested that a true IDDM susceptibility locus is located near CTLA4. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9259273+8817351" 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="#10" class="mim-tip-reference" title="Donner, H., Braun, J., Seidl, C., Rau, H., Finke, R., Ventz, M., Walfish, P. G., Usadel, K. H., Badenhoop, K. <strong>Codon 17 polymorphism of the cytotoxic T lymphocyte antigen 4 gene in Hashimoto's thyroiditis and Addison's disease.</strong> J. Clin. Endocr. Metab. 82: 4130-4132, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398726</a>] [<a href="https://doi.org/10.1210/jcem.82.12.4406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9398726">Donner et al. (1997)</a> found that patients with Hashimoto thyroiditis (<a href="/entry/140300">140300</a>) had a significantly higher number of the 49G allele compared to controls, both as homozygotes (22% vs 15%) and heterozygotes (53% vs 46%), and less of the A allele compared to controls as homozygotes (25% vs 39%; P less than 0.04). They also found that the phenotypic frequency for the G allele was significantly higher in patients (75%), compared with controls (61%), P less than 0.03. Whereas Addison disease (<a href="/entry/240200">240200</a>) subjects did not differ significantly from controls, those carrying the susceptibility marker, human leukocyte antigen DQA1*0501, had a significantly higher frequency of the G allele than controls with the same DQA1 allele (P less than 0.05). <a href="#10" class="mim-tip-reference" title="Donner, H., Braun, J., Seidl, C., Rau, H., Finke, R., Ventz, M., Walfish, P. G., Usadel, K. H., Badenhoop, K. <strong>Codon 17 polymorphism of the cytotoxic T lymphocyte antigen 4 gene in Hashimoto's thyroiditis and Addison's disease.</strong> J. Clin. Endocr. Metab. 82: 4130-4132, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398726</a>] [<a href="https://doi.org/10.1210/jcem.82.12.4406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9398726">Donner et al. (1997)</a> concluded that the 49G allele (ala17) of the CTLA4 gene conferred genetic susceptibility to Hashimoto thyroiditis, whereas this finding only applied to the subgroup of patients with Addison disease carrying DQA1*0501+. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9398726" 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="#48" class="mim-tip-reference" title="Vaidya, B., Imrie, H., Perros, P., Dickinson, J., McCarthy, M. I., Kendall-Taylor, P., Pearce, S. H. S. <strong>Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism confers susceptibility to thyroid associated orbitopathy.</strong> Lancet 354: 743-744, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10475192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10475192</a>] [<a href="https://doi.org/10.1016/S0140-6736(99)01465-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10475192">Vaidya et al. (1999)</a> presented evidence that the alanine-17 allele also confers susceptibility to thyroid-associated orbitopathy in patients with Graves disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10475192" 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="#37" class="mim-tip-reference" title="Rau, H., Braun, J., Donner, H., Seissler, J., Siegmund, T., Usadel, K. H., Badenhoop, K. <strong>The codon 17 polymorphism of the CTLA4 gene in type 2 diabetes mellitus.</strong> J. Clin. Endocr. Metab. 86: 653-655, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11158025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11158025</a>] [<a href="https://doi.org/10.1210/jcem.86.2.7204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11158025">Rau et al. (2001)</a> analyzed the CTLA4 49A/G polymorphism in 300 Caucasian patients with type 2 diabetes (<a href="/entry/125853">125853</a>) and 466 healthy controls. All patients were negative for glutamate decarboxylase and islet cell antibodies. The distribution of alleles and the genotypic and phenotypic frequencies were similar among patients and controls. However, analysis of clinical and biochemical parameters revealed a tendency of GG (alanine/alanine) toward younger age at disease manifestation, lower body mass index, and basal C-peptide level, as well as earlier start of insulin treatment and higher portion of patients on insulin. Patients with the AA genotype were significantly less likely to develop microangiopathic lesions. The authors concluded that CTLA4 ala17 does not represent a major risk factor for type II diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11158025" 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="#56" class="mim-tip-reference" title="Zalloua, P. A., Abchee, A., Shbaklo, H., Zreik, T. G., Terwedow, H., Halaby, G., Azar, S. T. <strong>Patients with early onset of type 1 diabetes have significantly higher GG genotype at position 49 of the CTLA4 gene.</strong> Hum. Immun. 65: 719-724, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15301861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15301861</a>] [<a href="https://doi.org/10.1016/j.humimm.2004.04.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15301861">Zalloua et al. (2004)</a> evaluated the role of the CTLA4 exon 1 A49G polymorphism as a risk factor for type 1 diabetes in the Lebanese population. The CTLA4 G allele was found to be more frequently present in patients with type 1 diabetes (32.4%) than in control individuals (24.5%). The GG genotype was also significantly higher among patients (12.6%) than in controls (4.2%). Furthermore, in HLA-DQB1*0201-positive patients with type 1 diabetes, the GG and AA genotypes were higher and lower, respectively, than those found in control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15301861" 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 metaanalysis of 7 published studies and their own study, <a href="#3" class="mim-tip-reference" title="Barreto, M., Santos, E., Ferreira, R., Fesel, C., Fontes, M. F., Pereira, C., Martins, B., Andreia, R., Viana, J. F., Crespo, F., Vasconcelos, C., Ferreira, C., Vicente, A. M. <strong>Evidence for CTLA4 as a susceptibility gene for systemic lupus erythematosus.</strong> Europ. J. Hum. Genet. 12: 620-626, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15138458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15138458</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201214" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15138458">Barreto et al. (2004)</a> examined the association between the 49A-G SNP and systemic lupus erythematosus (<a href="/entry/152700">152700</a>). The authors found that individuals with the GG genotype were at significantly higher risk of developing SLE; carriers of the A allele had a significantly lower risk of developing the disease, and the AA genotype acted as a protective genotype for SLE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15138458" 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 metaanalysis of 14 independent studies testing association between CTLA4 polymorphisms and SLE, <a href="#24" class="mim-tip-reference" title="Lee, Y. H., Harley, J. B., Nath, S. K. <strong>CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis.</strong> Hum. Genet. 116: 361-367, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15688186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15688186</a>] [<a href="https://doi.org/10.1007/s00439-004-1244-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15688186">Lee et al. (2005)</a> confirmed that the 49A-G polymorphism is significantly associated with SLE susceptibility, particularly in Asians. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15688186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Djilali-Saiah, I., Schmitz, J., Harfouch-Hammoud, E., Mougenot, J.-F., Bach, J.-F., Caillat-Zucman, S. <strong>CTLA-4 gene polymorphism is associated with predisposition to coeliac disease.</strong> Gut 43: 187-189, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10189842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10189842</a>] [<a href="https://doi.org/10.1136/gut.43.2.187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10189842">Djilali-Saiah et al. (1998)</a> found a significantly increased frequency of the 49A allele in 101 French Caucasian patients with celiac disease compared to controls (82.2% vs 65.8%, p less than 0.0001), reflecting the increased frequency of A/A homozygotes among patients compared with controls (68.3% vs 47.7%, p = 0.002). The effect remained after stratification of patients according to their DR-DQ phenotype. The authors concluded that the A allele of the CTLA4 position 49 polymorphism conferred an HLA-independent predisposition to celiac disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10189842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Naluai, A. T., Nilsson, S., Samuelsson, L., Gudjonsdottir, A. H., Ascher, H., Ek, J., Hallberg, B., Kristiansson, B., Martinsson, T., Nerman, O., Sollid, L. M., Wahlstrom, J. <strong>The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory diseases.</strong> Tissue Antigens 56: 350-355, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11098935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11098935</a>] [<a href="https://doi.org/10.1034/j.1399-0039.2000.560407.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11098935">Naluai et al. (2000)</a> analyzed the 49A/G polymorphism in 107 Swedish and Norwegian families with celiac disease and found a significant association, with preferential transmission of the 49A allele by the transmission disequilibrium test (p less than 0.007). Nonparametric linkage analysis yielded a score of 2.1 (p = 0.018), suggesting that the CTLA4 region is a susceptibility region in celiac disease. <a href="#31" class="mim-tip-reference" title="Naluai, A. T., Nilsson, S., Samuelsson, L., Gudjonsdottir, A. H., Ascher, H., Ek, J., Hallberg, B., Kristiansson, B., Martinsson, T., Nerman, O., Sollid, L. M., Wahlstrom, J. <strong>The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory diseases.</strong> Tissue Antigens 56: 350-355, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11098935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11098935</a>] [<a href="https://doi.org/10.1034/j.1399-0039.2000.560407.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11098935">Naluai et al. (2000)</a> noted that, of several chronic inflammatory diseases exhibiting associations to the CTLA4 49A/G polymorphism, celiac disease is the only one associated with the A allele, suggesting that the 49A/G alleles of CTLA4 are in linkage disequilibrium with 2 distinct disease-predisposing alleles with separate effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11098935" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs3087243 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3087243;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/rs3087243?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=rs3087243" 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=rs3087243" 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=RCV000018429 OR RCV000018430 OR RCV001254798 OR RCV001515646 OR RCV004707853" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018429, RCV000018430, RCV001254798, RCV001515646, RCV004707853" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018429...</a>
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<p><a href="#47" class="mim-tip-reference" title="Ueda, H., Howson, J. M. M., Esposito, L., Heward, J., Snook, H., Chamberlain, G., Rainbow, D. B., Hunter, K. M. D., Smith, A. N., DiGenova, G., Herr, M. H., Dahlman, I., and 41 others. <strong>Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease.</strong> Nature 423: 506-511, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12724780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12724780</a>] [<a href="https://doi.org/10.1038/nature01621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12724780">Ueda et al. (2003)</a> identified a series of single-nucleotide polymorphisms (SNPs) between 0.2 and 6.3 kb 3-prime of the end of the CTLA4 transcript. One was termed CT60 and encodes either a protective A/A genotype or a predisposing G/G genotype for autoimmune disease (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3087243;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3087243</a>). CT60 is a common SNP, with 63.4% of 1,316 Graves disease (<a href="/entry/275000">275000</a>) patient chromosomes and 53.2% of 1,646 control chromosomes having the susceptible G allele. Compared with the protective CT60 A/A genotype, the A/G and G/G genotypes had odds ratios of 1.59 (1.19-2.13) and 2.32 (1.71-3.15), respectively. In controls, the A/A, A/G, and G/G genotypes had frequencies of 22.8%, 48.0%, and 29.2%, and in Graves disease cases, 13.7%, 45.7%, and 40.6%, respectively. Conversely, relative to the disease-predisposing G/G genotype, A/G and A/A had odds ratios of 0.68 (0.54-0.86) and 0.43 (0.32-0.59), respectively. The CT60 SNP was also associated with autoimmune hypothyroidism, or Hashimoto thyroiditis (<a href="/entry/140300">140300</a>) to the same degree as Graves disease (odds ratio = 1.45 (1.17-1.80); p = 0.0005). However, the effect was much weaker in type I diabetes. <a href="#47" class="mim-tip-reference" title="Ueda, H., Howson, J. M. M., Esposito, L., Heward, J., Snook, H., Chamberlain, G., Rainbow, D. B., Hunter, K. M. D., Smith, A. N., DiGenova, G., Herr, M. H., Dahlman, I., and 41 others. <strong>Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease.</strong> Nature 423: 506-511, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12724780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12724780</a>] [<a href="https://doi.org/10.1038/nature01621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12724780">Ueda et al. (2003)</a> suggested the presence of a common Graves disease, type I diabetes (T1D12; <a href="/entry/601388">601388</a>), and autoimmune hypothyroidism locus in the 6.1-kb 3-prime region of CTLA4. Using a real-time PCR assay, <a href="#47" class="mim-tip-reference" title="Ueda, H., Howson, J. M. M., Esposito, L., Heward, J., Snook, H., Chamberlain, G., Rainbow, D. B., Hunter, K. M. D., Smith, A. N., DiGenova, G., Herr, M. H., Dahlman, I., and 41 others. <strong>Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease.</strong> Nature 423: 506-511, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12724780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12724780</a>] [<a href="https://doi.org/10.1038/nature01621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12724780">Ueda et al. (2003)</a> showed that the CT60 polymorphism determines the efficiency of the splicing and production of soluble CTLA4, with the CT60G disease-susceptibility haplotype producing less soluble CTLA4 transcript than the resistant CT60A haplotype. In a mouse model of type I diabetes, susceptibility was also associated with variation in CTLA4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12724780" 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="#49" class="mim-tip-reference" title="van Belzen, M. J., Mulder, C. J. J., Zhernakova, A., Pearson, P. L., Houwen, R. H. J., Wijmenga, C. <strong>CTLA4 +49A/G and CT60 polymorphisms in Dutch coeliac disease patients.</strong> Europ. J. Hum. Genet. 12: 782-785, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15199380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15199380</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15199380">Van Belzen et al. (2004)</a> genotyped 215 Dutch patients with celiac disease (<a href="/entry/609755">609755</a>) and 213 controls for the 49A-G (<a href="#0001">123890.0001</a>) and CT60 polymorphisms in the CTLA4 gene. They found no significant difference between patients and controls in the frequency of the 49G allele, but did find an increase in the frequency of the CT60 G allele in patients (p = 0.048). <a href="#49" class="mim-tip-reference" title="van Belzen, M. J., Mulder, C. J. J., Zhernakova, A., Pearson, P. L., Houwen, R. H. J., Wijmenga, C. <strong>CTLA4 +49A/G and CT60 polymorphisms in Dutch coeliac disease patients.</strong> Europ. J. Hum. Genet. 12: 782-785, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15199380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15199380</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15199380">Van Belzen et al. (2004)</a> concluded that CTLA4 is involved in the development of celiac disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15199380" 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 IMMUNE DYSREGULATION WITH AUTOIMMUNITY, IMMUNODEFICIENCY, AND LYMPHOPROLIFERATION</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs606231417 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231417;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=rs606231417" 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=rs606231417" 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=RCV000148290 OR RCV000788671 OR RCV002515995 OR RCV005016468" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000148290, RCV000788671, RCV002515995, RCV005016468" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000148290...</a>
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<p>In a father and daughter with immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL; <a href="/entry/616100">616100</a>), <a href="#23" class="mim-tip-reference" title="Kuehn, H. S., Ouyang W., Lo, B., Deenick, E. K., Niemela, J. E., Avery, D. T., Schickel, J.-N., Tran, D. Q., Stoddard, J., Zhang, Y., Frucht, D. M., Dumitriu, B., and 24 others. <strong>Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.</strong> Science 345: 1623-1627, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25213377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25213377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25213377[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1255904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25213377">Kuehn et al. (2014)</a> identified a heterozygous c.151C-T transition in exon 2 of the CTLA4 gene, resulting in an arg51-to-ter (R51X) substitution in the ligand-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Sequencing Project databases. Analysis of patient cells showed that the mutant mRNA was degraded, consistent with nonsense-mediated mRNA decay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25213377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs606231418 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231418;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/rs606231418?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=rs606231418" 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=rs606231418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 38-year-old man with immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL; <a href="/entry/616100">616100</a>), <a href="#23" class="mim-tip-reference" title="Kuehn, H. S., Ouyang W., Lo, B., Deenick, E. K., Niemela, J. E., Avery, D. T., Schickel, J.-N., Tran, D. Q., Stoddard, J., Zhang, Y., Frucht, D. M., Dumitriu, B., and 24 others. <strong>Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.</strong> Science 345: 1623-1627, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25213377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25213377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25213377[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1255904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25213377">Kuehn et al. (2014)</a> identified a heterozygous 1-bp deletion (c.75delG) in exon 1 of the CTLA4 gene, resulting in a frameshift and premature termination (Leu28PhefsTer44). The mutation was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Sequencing Project databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25213377" 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 IMMUNE DYSREGULATION WITH AUTOIMMUNITY, IMMUNODEFICIENCY, AND LYMPHOPROLIFERATION</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs606231419 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231419;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=rs606231419" 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=rs606231419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a father and son with immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL; <a href="/entry/616100">616100</a>), <a href="#23" class="mim-tip-reference" title="Kuehn, H. S., Ouyang W., Lo, B., Deenick, E. K., Niemela, J. E., Avery, D. T., Schickel, J.-N., Tran, D. Q., Stoddard, J., Zhang, Y., Frucht, D. M., Dumitriu, B., and 24 others. <strong>Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.</strong> Science 345: 1623-1627, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25213377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25213377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25213377[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1255904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25213377">Kuehn et al. (2014)</a> identified a heterozygous G-to-C transversion in intron 3 of the CTLA4 gene (c.567+5G-C), resulting in the absence of exon 3 and the production of only a soluble form of CTLA4; full-length mRNA encoding the membrane-bound form was decreased. The mutation was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Sequencing Project databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25213377" 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 IMMUNE DYSREGULATION WITH AUTOIMMUNITY, IMMUNODEFICIENCY, AND LYMPHOPROLIFERATION</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000148293" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000148293" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000148293</a>
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<p>In 5 affected members of a large family with immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL; <a href="/entry/616100">616100</a>), <a href="#41" class="mim-tip-reference" title="Schubert, D., Bode, C., Kenefeck, R., Hou, T. Z., Wing, J. B., Kennedy, A., Bulashevska, A., Petersen, B.-S., Schaffer, A. A., Gruning, B. A., Unger, S., Frede, N., and 28 others. <strong>Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.</strong> Nature Med. 20: 1410-1416, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25329329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25329329</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25329329[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.3746" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25329329">Schubert et al. (2014)</a> identified a heterozygous c.105C-A transversion in exon 1 of the CTLA4 gene, resulting in a cys35-to-ter (C35X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP database. Six unaffected family members also carried the mutation, consistent with incomplete penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25329329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs606231421 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231421;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=rs606231421" 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=rs606231421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family with immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL; <a href="/entry/616100">616100</a>), <a href="#41" class="mim-tip-reference" title="Schubert, D., Bode, C., Kenefeck, R., Hou, T. Z., Wing, J. B., Kennedy, A., Bulashevska, A., Petersen, B.-S., Schaffer, A. A., Gruning, B. A., Unger, S., Frede, N., and 28 others. <strong>Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.</strong> Nature Med. 20: 1410-1416, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25329329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25329329</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25329329[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.3746" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25329329">Schubert et al. (2014)</a> identified a heterozygous G-to-T transversion in intron 1 of the CTLA4 gene (c.110+1G-T), resulting in disruption of a donor splice site and predicted to result in haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25329329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs606231422 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231422;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=rs606231422" 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=rs606231422" 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=RCV000148295 OR RCV001311981" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000148295, RCV001311981" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000148295...</a>
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<p>In 2 sibs with immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL; <a href="/entry/616100">616100</a>), <a href="#41" class="mim-tip-reference" title="Schubert, D., Bode, C., Kenefeck, R., Hou, T. Z., Wing, J. B., Kennedy, A., Bulashevska, A., Petersen, B.-S., Schaffer, A. A., Gruning, B. A., Unger, S., Frede, N., and 28 others. <strong>Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.</strong> Nature Med. 20: 1410-1416, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25329329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25329329</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25329329[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.3746" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25329329">Schubert et al. (2014)</a> identified a heterozygous c.208C-T transition in the CTLA4 gene, resulting in an arg70-to-trp (R70W) substitution at a highly conserved residue in the extracellular domain, predicted to interfere with ligand binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25329329" 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>REFERENCES</strong>
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|
|
<a id="1" class="mim-anchor"></a>
|
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<a id="Abrams1999" class="mim-anchor"></a>
|
|
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|
|
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|
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Abrams, J. R., Lebwohl, M. G., Guzzo, C. A., Jegasothy, B. V., Goldfarb, M. T., Goffe, B. S., Menter, A., Lowe, N. J., Krueger, G., Brown, M. J., Weiner, R. S., Birkhofer, M. J., Warner, G. L., Berry, K. K., Linsley, P. S., Krueger, J. G., Ochs, H. D., Kelley, S. L., Kang, S.
|
|
<strong>CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris.</strong>
|
|
J. Clin. Invest. 103: 1243-1252, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10225967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10225967</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10225967[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=10225967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
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[<a href="https://doi.org/10.1172/JCI5857" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
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|
|
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|
|
|
|
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|
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|
|
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|
|
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|
|
Allison, J. P., Krummel, M. F.
|
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<strong>The yin and yang of T cell costimulation.</strong>
|
|
Science 270: 932-933, 1995.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7481795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7481795</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7481795" 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.270.5238.932" target="_blank">Full Text</a>]
|
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|
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|
|
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|
|
|
|
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|
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|
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|
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|
|
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|
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Barreto, M., Santos, E., Ferreira, R., Fesel, C., Fontes, M. F., Pereira, C., Martins, B., Andreia, R., Viana, J. F., Crespo, F., Vasconcelos, C., Ferreira, C., Vicente, A. M.
|
|
<strong>Evidence for CTLA4 as a susceptibility gene for systemic lupus erythematosus.</strong>
|
|
Europ. J. Hum. Genet. 12: 620-626, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15138458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15138458</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15138458" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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|
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Bour-Jordan, H., Grogan, J. L., Tang, Q., Auger, J. A., Locksley, R. M., Bluestone, J. A.
|
|
<strong>CTLA-4 regulates the requirement for cytokine-induced signals in T(H)2 lineage commitment.</strong>
|
|
Nature Immun. 4: 182-188, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12524538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12524538</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12524538" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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|
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|
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Buonavista, N., Balzano, C., Pontarotti, P., Le Paslier, D., Golstein, P.
|
|
<strong>Molecular linkage of the human CTLA4 and CD28 Ig-superfamily genes in yeast artificial chromosomes.</strong>
|
|
Genomics 13: 856-861, 1992.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1322357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1322357</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1322357" 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/10.1016/0888-7543(92)90169-s" target="_blank">Full Text</a>]
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|
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Chain, J. L., Martin, A. K., Mack, D. G., Maier, L. A., Palmer, B. E., Fontenot, A. P.
|
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<strong>Impaired function of CTLA-4 in the lungs of patients with chronic beryllium disease contributes to persistent inflammation.</strong>
|
|
J. Immun. 191: 1648-1656, 2013.
|
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|
|
|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23851684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23851684</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23851684[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=23851684" 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.1300282" target="_blank">Full Text</a>]
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Chu, X., Pan, C.-M., Zhao, S.-X., Liang, J., Gao, G.-Q., Zhang, X.-M., Yuan, G.-Y., Li, C.-G., Xue, L.-Q., Shen, M., Liu, W., Xie, F., and 37 others.
|
|
<strong>A genome-wide association study identifies two new risk loci for Graves' disease.</strong>
|
|
Nature Genet. 43: 897-901, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21841780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21841780</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21841780" 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/ng.898" target="_blank">Full Text</a>]
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Dariavach, P., Mattei, M.-G., Golstein, P., Lefranc, M.-P.
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<strong>Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains.</strong>
|
|
Europ. J. Immun. 18: 1901-1905, 1988.
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|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3220103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3220103</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3220103" 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/10.1002/eji.1830181206" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="9" class="mim-anchor"></a>
|
|
<a id="Djilali-Saiah1998" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Djilali-Saiah, I., Schmitz, J., Harfouch-Hammoud, E., Mougenot, J.-F., Bach, J.-F., Caillat-Zucman, S.
|
|
<strong>CTLA-4 gene polymorphism is associated with predisposition to coeliac disease.</strong>
|
|
Gut 43: 187-189, 1998.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10189842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10189842</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10189842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1136/gut.43.2.187" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="10" class="mim-anchor"></a>
|
|
<a id="Donner1997" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Donner, H., Braun, J., Seidl, C., Rau, H., Finke, R., Ventz, M., Walfish, P. G., Usadel, K. H., Badenhoop, K.
|
|
<strong>Codon 17 polymorphism of the cytotoxic T lymphocyte antigen 4 gene in Hashimoto's thyroiditis and Addison's disease.</strong>
|
|
J. Clin. Endocr. Metab. 82: 4130-4132, 1997.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398726</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9398726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1210/jcem.82.12.4406" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="11" class="mim-anchor"></a>
|
|
<a id="Fallarino2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Fallarino, F., Grohmann, U., Hwang, K. W., Orabona, C., Vacca, C., Bianchi, R., Belladonna, M. L., Fioretti, M. C., Alegre, M.-L., Puccetti, P.
|
|
<strong>Modulation of tryptophan catabolism by regulatory T cells.</strong>
|
|
Nature Immun. 4: 1206-1212, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14578884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14578884</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14578884" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/ni1003" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="12" class="mim-anchor"></a>
|
|
<a id="Gozalo-Sanmillan2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Gozalo-Sanmillan, S., McNally, J. M., Lin, M. Y., Chambers, C. A., Berg, L. J.
|
|
<strong>Cutting edge: two distinct mechanisms lead to impaired T cell homeostasis in Janus kinase 3- and CTLA-4-deficient mice.</strong>
|
|
J. Immun. 166: 727-730, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11145642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11145642</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11145642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.4049/jimmunol.166.2.727" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="13" class="mim-anchor"></a>
|
|
<a id="Grohmann2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Grohmann, U., Orabona, C., Fallarino, F., Vacca, C., Calcinaro, F., Falorni, A., Candeloro, P., Belladonna, M. L., Bianchi, R., Fioretti, M. C., Puccetti, P.
|
|
<strong>CTLA-4-Ig regulates tryptophan catabolism in vivo.</strong>
|
|
Nature Immun. 3: 1097-1101, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12368911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12368911</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12368911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/ni846" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="14" class="mim-anchor"></a>
|
|
<a id="Harper1991" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Harper, K., Balzano, C., Rouvier, E., Mattei, M.-G., Luciani, M.-F., Golstein, P.
|
|
<strong>CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location.</strong>
|
|
J. Immun. 147: 1037-1044, 1991.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1713603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1713603</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1713603" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="15" class="mim-anchor"></a>
|
|
<a id="Heward1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Heward, J. M., Allahabadia, A., Armitage, M., Hattersley, A., Dodson, P. M., Macleod, K., Carr-Smith, J., Daykin, J., Daly, A., Sheppard, M. C., Holder, R. L., Barnett, A. H., Franklyn, J. A., Gough, S. C. L.
|
|
<strong>The development of Graves' disease and the CTLA-4 gene on chromosome 2q33.</strong>
|
|
J. Clin. Endocr. Metab. 84: 2398-2401, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10404810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10404810</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10404810" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1210/jcem.84.7.5820" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="16" class="mim-anchor"></a>
|
|
<a id="Howard1991" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Howard, T. A., Rochelle, J. M., Seldin, M. F.
|
|
<strong>Cd28 and Ctla-4, two related members of the Ig supergene family, are tightly linked on proximal mouse chromosome 1.</strong>
|
|
Immunogenetics 33: 74-76, 1991.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671668</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1671668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1007/BF00211698" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="17" class="mim-anchor"></a>
|
|
<a id="Hudson2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hudson, L. L., Rocca, K., Song, Y. W., Pandey, J. P.
|
|
<strong>CTLA-4 gene polymorphisms in systemic lupus erythematosus: a highly significant association with a determinant in the promoter region.</strong>
|
|
Hum. Genet. 111: 452-455, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12384790/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12384790</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12384790" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1007/s00439-002-0807-2" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="18" class="mim-anchor"></a>
|
|
<a id="Hunt2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Hunt, K. A., McGovern, D. P. B., Kumar, P. J., Ghosh, S., Travis, S. P. L., Walters, J. R. F., Jewell, D. P., Playford, R. J., van Heel, D. A.
|
|
<strong>A common CTLA4 haplotype associated with coeliac disease.</strong>
|
|
Europ. J. Hum. Genet. 13: 440-444, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15657618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15657618</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15657618" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/sj.ejhg.5201357" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="19" class="mim-anchor"></a>
|
|
<a id="Kaufmann2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kaufmann, D. E., Kavanagh, D. G., Pereyra, F., Zaunders, J. J., Mackey, E. W., Miura, T., Palmer, S., Brockman, M., Rathod, A., Piechocka-Trocha, A., Baker, B., Zhu, B., and 9 others.
|
|
<strong>Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction.</strong>
|
|
Nature Immun. 8: 1246-1254, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17906628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17906628</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17906628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/ni1515" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="20" class="mim-anchor"></a>
|
|
<a id="Kavvoura2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kavvoura, F. K., Akamizu, T., Awata, T., Ban, Y., Chistiakov, D. A., Frydecka, I., Ghaderi, A., Gough, S. C., Hiromatsu, Y., Ploski, R., Wang, P.-W., Ban, Y., and 16 others.
|
|
<strong>Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: a meta-analysis.</strong>
|
|
J. Clin. Endocr. Metab. 92: 3162-3170, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17504905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17504905</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17504905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1210/jc.2007-0147" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="21" class="mim-anchor"></a>
|
|
<a id="Kinjo2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kinjo, Y., Takasu, N., Komiya, I., Tomoyose, T., Takara, M., Kouki, T., Shimajiri, Y., Yabiku, K., Yoshimura, H.
|
|
<strong>Remission of Graves' hyperthyroidism and A/G polymorphism at position 49 in exon 1 of cytotoxic T lymphocyte-associated molecule-4 gene.</strong>
|
|
J. Clin. Endocr. Metab. 87: 2593-2596, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050220</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050220" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1210/jcem.87.6.8612" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="22" class="mim-anchor"></a>
|
|
<a id="Kouki2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kouki, T., Sawai, Y., Gardine, C. A., Fisfalen, M.-E., Alegre, M.-L., DeGroot, L. J.
|
|
<strong>CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves' disease.</strong>
|
|
J. Immun. 165: 6606-6611, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11086105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11086105</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11086105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.4049/jimmunol.165.11.6606" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="23" class="mim-anchor"></a>
|
|
<a id="Kuehn2014" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kuehn, H. S., Ouyang W., Lo, B., Deenick, E. K., Niemela, J. E., Avery, D. T., Schickel, J.-N., Tran, D. Q., Stoddard, J., Zhang, Y., Frucht, D. M., Dumitriu, B., and 24 others.
|
|
<strong>Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.</strong>
|
|
Science 345: 1623-1627, 2014.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25213377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25213377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25213377[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=25213377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1255904" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="24" class="mim-anchor"></a>
|
|
<a id="Lee2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lee, Y. H., Harley, J. B., Nath, S. K.
|
|
<strong>CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis.</strong>
|
|
Hum. Genet. 116: 361-367, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15688186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15688186</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15688186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1007/s00439-004-1244-1" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="25" class="mim-anchor"></a>
|
|
<a id="Ling1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ling, V., Wu, P. W., Finnerty, H. F., Sharpe, A. H., Gray, G. S., Collins, M.
|
|
<strong>Complete sequence determination of the mouse and human CTLA4 gene loci: cross-species DNA sequence similarity beyond exon borders.</strong>
|
|
Genomics 60: 341-355, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10493833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10493833</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10493833" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1006/geno.1999.5930" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="26" class="mim-anchor"></a>
|
|
<a id="Linsley1995" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Linsley, P. S., Nadler, S. G., Bajorath, J., Peach, R., Leung, H. T., Rogers, J., Bradshaw, J., Stebbins, M., Leytze, G., Brady, W., Malacko, A. R., Marquardt, H., Shaw, S.-Y.
|
|
<strong>Binding stoichiometry of the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) : a disulfide-linked homodimer binds two CD86 molecules.</strong>
|
|
J. Biol. Chem. 270: 15417-15424, 1995.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7541042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7541042</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7541042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1074/jbc.270.25.15417" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="27" class="mim-anchor"></a>
|
|
<a id="Lo2015" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lo, B., Zhang, K., Lu, W., Zheng, L., Zhang, Q., Kanellopoulou, C., Zhang, Y., Liu, Z., Fritz, J. M., Marsh, R., Husami, A., Kissell, D., and 21 others.
|
|
<strong>Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy.</strong>
|
|
Science 349: 436-440, 2015.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26206937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26206937</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26206937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.aaa1663" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="28" class="mim-anchor"></a>
|
|
<a id="Lohmueller2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lohmueller, K. E., Pearce, C. L., Pike, M., Lander, E. S., Hirschhorn, J. N.
|
|
<strong>Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease.</strong>
|
|
Nature Genet. 33: 177-182, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12524541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12524541</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12524541" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/ng1071" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="29" class="mim-anchor"></a>
|
|
<a id="Magistrelli1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Magistrelli, G., Jeannin, P., Herbault, N., Benoit de Coignac, A., Gauchat, J.-F., Bonnefoy, J.-Y., Delneste, Y.
|
|
<strong>A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells.</strong>
|
|
Europ. J. Immun. 29: 3596-3602, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10556814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10556814</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10556814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/(SICI)1521-4141(199911)29:11<3596::AID-IMMU3596>3.0.CO;2-Y" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="30" class="mim-anchor"></a>
|
|
<a id="Marron1997" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Marron, M. P., Raffel, L. J., Garchon, H.-J., Jacob, C. O., Serrano-Rios, M., Martinez Larrad, M. T., Teng, W.-P., Park, Y., Zhang, Z.-X., Goldstein, D. R., Tao, Y.-W., Beaurain, G., Bach, J.-F., Huang, H.-S., Luo, D.-F., Zeidler, A., Rotter, J. I., Yang, M. C. K., Modilevsky, T., Maclaren, N. K., She, J.-X.
|
|
<strong>Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups.</strong>
|
|
Hum. Molec. Genet. 6: 1275-1282, 1997.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9259273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9259273</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9259273" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/6.8.1275" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="31" class="mim-anchor"></a>
|
|
<a id="Naluai2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Naluai, A. T., Nilsson, S., Samuelsson, L., Gudjonsdottir, A. H., Ascher, H., Ek, J., Hallberg, B., Kristiansson, B., Martinsson, T., Nerman, O., Sollid, L. M., Wahlstrom, J.
|
|
<strong>The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory diseases.</strong>
|
|
Tissue Antigens 56: 350-355, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11098935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11098935</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11098935" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1034/j.1399-0039.2000.560407.x" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="32" class="mim-anchor"></a>
|
|
<a id="Nistico1996" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Nistico, L., Buzzetti, R., Pritchard, L. E., Van der Auwera, B., Giovannini, C., Bosi, E., Martinez Larrad, M. T., Serrano Rios, M., Chow, C. C., Cockram, C. S., Jacobs, K., Mijovic, C., Bain, S. C., Barnett, A. H., Vandewalle, C. L., Schuit, F., Gorus, F. K., Belgian Diabetes Registry, Tosi, R., Pozzilli, P., Todd, J. A.
|
|
<strong>The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes.</strong>
|
|
Hum. Molec. Genet. 5: 1075-1080, 1996.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8817351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8817351</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8817351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/5.7.1075" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="33" class="mim-anchor"></a>
|
|
<a id="Oaks2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Oaks, M. K., Hallett, K. M., Penwell, R. T., Stauber, E. C., Warren, S. J., Tector, A. J.
|
|
<strong>A native soluble form of CTLA-4.</strong>
|
|
Cell. Immun. 201: 144-153, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10831323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10831323</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10831323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1006/cimm.2000.1649" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="34" class="mim-anchor"></a>
|
|
<a id="Oaks2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Oaks, M. K., Hallett, K. M.
|
|
<strong>Cutting edge: a soluble form of CTLA-4 in patients with autoimmune thyroid disease.</strong>
|
|
J. Immun. 164: 5015-5018, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10799854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10799854</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10799854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.4049/jimmunol.164.10.5015" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="35" class="mim-anchor"></a>
|
|
<a id="Ostrov2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ostrov, D. A., Shi, W., Schwartz, J.-C. D., Almo, S. C., Nathenson, S. G.
|
|
<strong>Structure of murine CTLA-4 and its role in modulating T cell responsiveness.</strong>
|
|
Science 290: 816-819, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11052947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11052947</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11052947" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.290.5492.816" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="36" class="mim-anchor"></a>
|
|
<a id="Qureshi2011" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Qureshi, O. S., Zheng, Y., Nakamura, K., Attridge, K., Manzotti, C., Schmidt, E. M., Baker, J., Jeffery, L. E., Kaur, S., Briggs, Z., Hou, T. Z., Futter, C. E., Anderson, G., Walker, L. S. K., Sansom, D. M.
|
|
<strong>Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.</strong>
|
|
Science 332: 600-603, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21474713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21474713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21474713[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=21474713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1202947" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="37" class="mim-anchor"></a>
|
|
<a id="Rau2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Rau, H., Braun, J., Donner, H., Seissler, J., Siegmund, T., Usadel, K. H., Badenhoop, K.
|
|
<strong>The codon 17 polymorphism of the CTLA4 gene in type 2 diabetes mellitus.</strong>
|
|
J. Clin. Endocr. Metab. 86: 653-655, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11158025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11158025</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11158025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1210/jcem.86.2.7204" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="38" class="mim-anchor"></a>
|
|
<a id="Reiser1996" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Reiser, H., Stadecker, M. J.
|
|
<strong>Costimulatory B7 molecules in the pathogenesis of infectious and autoimmune diseases.</strong>
|
|
New Eng. J. Med. 335: 1369-1377, 1996.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8857022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8857022</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8857022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1056/NEJM199610313351807" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="39" class="mim-anchor"></a>
|
|
<a id="Sayegh1998" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Sayegh, M. H., Turka, L. A.
|
|
<strong>The role of T-cell costimulatory activation pathways in transplant rejection.</strong>
|
|
New Eng. J. Med. 338: 1813-1821, 1998.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9632449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9632449</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9632449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1056/NEJM199806183382506" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="40" class="mim-anchor"></a>
|
|
<a id="Schneider2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Schneider, H., Downey, J., Smith, A., Zinselmeyer, B. H., Rush, C., Brewer, J. M., Wei, B., Hogg, N., Garside, P., Rudd, C. E.
|
|
<strong>Reversal of the TCR stop signal by CTLA-4.</strong>
|
|
Science 313: 1972-1975, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16931720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16931720</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16931720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1131078" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="41" class="mim-anchor"></a>
|
|
<a id="Schubert2014" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Schubert, D., Bode, C., Kenefeck, R., Hou, T. Z., Wing, J. B., Kennedy, A., Bulashevska, A., Petersen, B.-S., Schaffer, A. A., Gruning, B. A., Unger, S., Frede, N., and 28 others.
|
|
<strong>Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.</strong>
|
|
Nature Med. 20: 1410-1416, 2014.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25329329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25329329</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25329329[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=25329329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nm.3746" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="42" class="mim-anchor"></a>
|
|
<a id="Schwartz2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Schwartz, J.-C. D., Zhang, X., Fedorov, A. A., Nathenson, S. G., Almo, S. C.
|
|
<strong>Structural basis for co-stimulation by the human CTLA-4/B7-2 complex.</strong>
|
|
Nature 410: 604-608, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11279501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11279501</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11279501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/35069112" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="43" class="mim-anchor"></a>
|
|
<a id="Shahinian1993" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Shahinian, A., Pfeffer, K., Lee, K. P., Kundig, T. M., Kishihara, K., Wakeham, A., Kawai, K., Ohashi, P. S., Thompson, C. B., Mak, T. W.
|
|
<strong>Differential T cell costimulatory requirements in CD28-deficient mice.</strong>
|
|
Science 261: 609-612, 1993.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7688139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7688139</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7688139" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.7688139" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="44" class="mim-anchor"></a>
|
|
<a id="Stamper2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Stamper, C. C., Zhang, Y., Tobin, J. F., Erbe, D. V., Ikemizu, S., Davis, S. J., Stahl, M. L., Seehra, J., Somers, W. S., Mosyak, L.
|
|
<strong>Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses.</strong>
|
|
Nature 410: 608-611, 2001. Note: Erratum: Nature 411: 617 only, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11279502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11279502</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11279502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/35069118" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="45" class="mim-anchor"></a>
|
|
<a id="Thio2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Thio, C. L., Mosbruger, T. L., Kaslow, R. A., Karp, C. L., Strathdee, S. A., Vlahov, D., O'Brien, S. J., Astemborski, J., Thomas, D. L.
|
|
<strong>Cytotoxic T-lymphocyte antigen 4 gene and recovery from hepatitis B virus infection.</strong>
|
|
J. Virol. 78: 11258-11262, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15452244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15452244</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15452244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1128/JVI.78.20.11258-11262.2004" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="46" class="mim-anchor"></a>
|
|
<a id="Tomer2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Tomer, Y., Greenberg, D. A., Barbesino, G., Concepcion, E., Davies, T. F.
|
|
<strong>CTLA-4 and not CD28 is a susceptibility gene for thyroid autoantibody production.</strong>
|
|
J. Clin. Endocr. Metab. 86: 1687-1693, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11297604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11297604</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11297604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1210/jcem.86.4.7372" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="47" class="mim-anchor"></a>
|
|
<a id="Ueda2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ueda, H., Howson, J. M. M., Esposito, L., Heward, J., Snook, H., Chamberlain, G., Rainbow, D. B., Hunter, K. M. D., Smith, A. N., DiGenova, G., Herr, M. H., Dahlman, I., and 41 others.
|
|
<strong>Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease.</strong>
|
|
Nature 423: 506-511, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12724780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12724780</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12724780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature01621" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="48" class="mim-anchor"></a>
|
|
<a id="Vaidya1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Vaidya, B., Imrie, H., Perros, P., Dickinson, J., McCarthy, M. I., Kendall-Taylor, P., Pearce, S. H. S.
|
|
<strong>Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism confers susceptibility to thyroid associated orbitopathy.</strong>
|
|
Lancet 354: 743-744, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10475192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10475192</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10475192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/S0140-6736(99)01465-8" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="49" class="mim-anchor"></a>
|
|
<a id="van Belzen2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
van Belzen, M. J., Mulder, C. J. J., Zhernakova, A., Pearson, P. L., Houwen, R. H. J., Wijmenga, C.
|
|
<strong>CTLA4 +49A/G and CT60 polymorphisms in Dutch coeliac disease patients.</strong>
|
|
Europ. J. Hum. Genet. 12: 782-785, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15199380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15199380</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15199380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/sj.ejhg.5201165" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="50" class="mim-anchor"></a>
|
|
<a id="Vetizou2015" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Vetizou, M., Pitt, J. M., Daillere, R., Lepage, P., Waldschmitt, N., Flament, C., Rusakiewicz, S., Routy, B., Roberti, M. P., Duong, C. P. M., Poirier-Colame, V., Roux, A., and 26 others.
|
|
<strong>Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.</strong>
|
|
Science 350: 1079-1084, 2015.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26541610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26541610</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26541610[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=26541610" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.aad1329" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="51" class="mim-anchor"></a>
|
|
<a id="vom Berg2013" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
vom Berg, J., Vrohlings, M., Haller, S., Haimovici, A., Kulig, P., Sledzinska, A., Weller, M., Becher, B.
|
|
<strong>Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection.</strong>
|
|
J. Exp. Med. 210: 2803-2811, 2013.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24277150/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24277150</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24277150[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=24277150" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1084/jem.20130678" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="52" class="mim-anchor"></a>
|
|
<a id="Wang2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wang, P.-W., Chen, I.-Y., Liu, R.-T., Hsieh, C.-J., Hsi, E., Juo, S.-H. H.
|
|
<strong>Cytotoxic T lymphocyte-associated molecule-4 gene polymorphism and hyperthyroid Graves' disease relapse after antithyroid drug withdrawal: a follow-up study.</strong>
|
|
J. Clin. Endocr. Metab. 92: 2513-2518, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17426089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17426089</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17426089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1210/jc.2006-2761" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="53" class="mim-anchor"></a>
|
|
<a id="Wang2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wang, P.-W., Liu, R.-T., Juo, S.-H. H., Wang, S.-T., Hu, Y.-H., Hsieh, C.-J., Chen, M.-H., Chen, I.-Y., Wu, C.-L.
|
|
<strong>Cytotoxic T lymphocyte-associated molecule-4 polymorphism and relapse of Graves' hyperthyroidism after antithyroid withdrawal.</strong>
|
|
J. Clin. Endocr. Metab. 89: 169-173, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14715845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14715845</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14715845" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1210/jc.2003-030854" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="54" class="mim-anchor"></a>
|
|
<a id="Waterhouse1995" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Waterhouse, P., Penninger, J. M., Timms, E., Wakeham, A., Shahinian, A., Lee, K. P., Thompson, C. B., Griesser, H., Mak, T. W.
|
|
<strong>Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4.</strong>
|
|
Science 270: 985-988, 1995.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7481803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7481803</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7481803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.270.5238.985" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="55" class="mim-anchor"></a>
|
|
<a id="Wing2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T., Sakaguchi, S.
|
|
<strong>CTLA-4 control over Foxp3+ regulatory T cell function.</strong>
|
|
Science 322: 271-275, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18845758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18845758</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18845758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1160062" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="56" class="mim-anchor"></a>
|
|
<a id="Zalloua2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Zalloua, P. A., Abchee, A., Shbaklo, H., Zreik, T. G., Terwedow, H., Halaby, G., Azar, S. T.
|
|
<strong>Patients with early onset of type 1 diabetes have significantly higher GG genotype at position 49 of the CTLA4 gene.</strong>
|
|
Hum. Immun. 65: 719-724, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15301861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15301861</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15301861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.humimm.2004.04.007" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="57" class="mim-anchor"></a>
|
|
<a id="Zhernakova2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Zhernakova, A., Eerligh, P., Barrera, P., Wesoly, J. Z., Huizinga, T. W. J., Roep, B. O., Wijmenga, C., Koeleman, B. P. C.
|
|
<strong>CTLA4 is differentially associated with autoimmune diseases in the Dutch population.</strong>
|
|
Hum. Genet. 118: 58-66, 2005. Note: Erratum: Hum. Genet. 119: 225 only, 2006.
|
|
|
|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16025348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16025348</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16025348" 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/10.1007/s00439-005-0006-z" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 09/13/2016
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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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Ada Hamosh - updated : 12/01/2015<br>Cassandra L. Kniffin - updated : 12/1/2014<br>Paul J. Converse - updated : 10/17/2014<br>Paul J. Converse - updated : 7/8/2014<br>Ada Hamosh - updated : 10/17/2011<br>Ada Hamosh - updated : 6/21/2011<br>Paul J. Converse - updated : 11/7/2008<br>John A. Phillips, III - updated : 10/16/2008<br>Paul J. Converse - updated : 9/11/2008<br>John A. Phillips, III - updated : 3/24/2008<br>Paul J. Converse - updated : 11/3/2006<br>Ada Hamosh - updated : 11/2/2006<br>Marla J. F. O'Neill - updated : 4/19/2006<br>Victor A. McKusick - updated : 1/30/2006<br>Marla J. F. O'Neill - updated : 12/28/2005<br>Marla J. F. O'Neill - updated : 6/21/2005<br>Victor A. McKusick - updated : 4/26/2005<br>Cassandra L. Kniffin - reorganized : 1/25/2005<br>Cassandra L. Kniffin - updated : 1/12/2005<br>Marla J. F. O'Neill - updated : 10/18/2004<br>Paul J. Converse - updated : 11/5/2003<br>Ada Hamosh - updated : 5/1/2003<br>Victor A. McKusick - updated : 1/30/2003<br>John A. Phillips, III - updated : 1/30/2003<br>Paul J. Converse - updated : 1/16/2003<br>Paul J. Converse - updated : 10/11/2002<br>John A. Phillips, III - updated : 10/24/2001<br>John A. Phillips, III - updated : 7/26/2001<br>Paul J. Converse - updated : 7/18/2001<br>Paul J. Converse - updated : 4/4/2001<br>Paul J. Converse - updated : 2/21/2001<br>Paul J. Converse - updated : 11/2/2000<br>Paul J. Converse - updated : 7/5/2000<br>John A. Phillips, III - updated : 3/6/2000<br>Victor A. McKusick - updated : 12/22/1999<br>Victor A. McKusick - updated : 7/22/1999<br>Victor A. McKusick - updated : 5/20/1999<br>Paul Brennan -updated : 12/15/1998<br>John A. Phillips, III - updated : 5/21/1998<br>Victor A. McKusick - updated : 8/22/1997<br>Alan F. Scott - updated : 11/16/1995
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/15/1989
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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 : 10/29/2021
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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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carol : 09/05/2020<br>carol : 09/05/2020<br>carol : 09/03/2020<br>carol : 09/14/2016<br>alopez : 09/13/2016<br>alopez : 12/01/2015<br>mcolton : 12/5/2014<br>carol : 12/1/2014<br>mcolton : 12/1/2014<br>ckniffin : 12/1/2014<br>mgross : 10/21/2014<br>mcolton : 10/17/2014<br>carol : 9/4/2014<br>mgross : 7/9/2014<br>mcolton : 7/8/2014<br>carol : 12/9/2013<br>ckniffin : 12/5/2013<br>alopez : 10/17/2011<br>alopez : 6/21/2011<br>terry : 5/17/2011<br>joanna : 8/18/2010<br>wwang : 8/18/2009<br>ckniffin : 8/6/2009<br>carol : 2/19/2009<br>carol : 1/7/2009<br>mgross : 11/10/2008<br>terry : 11/7/2008<br>alopez : 10/16/2008<br>alopez : 10/16/2008<br>mgross : 9/12/2008<br>mgross : 9/12/2008<br>terry : 9/11/2008<br>terry : 6/6/2008<br>carol : 3/24/2008<br>alopez : 3/10/2008<br>terry : 5/7/2007<br>mgross : 11/3/2006<br>mgross : 11/3/2006<br>mgross : 11/3/2006<br>alopez : 11/2/2006<br>wwang : 5/18/2006<br>ckniffin : 5/17/2006<br>ckniffin : 5/17/2006<br>wwang : 4/20/2006<br>terry : 4/19/2006<br>joanna : 3/17/2006<br>carol : 2/16/2006<br>terry : 1/30/2006<br>wwang : 1/5/2006<br>terry : 12/28/2005<br>terry : 9/27/2005<br>wwang : 7/1/2005<br>wwang : 6/29/2005<br>terry : 6/21/2005<br>tkritzer : 4/29/2005<br>terry : 4/26/2005<br>tkritzer : 3/7/2005<br>terry : 2/7/2005<br>carol : 1/25/2005<br>carol : 1/25/2005<br>ckniffin : 1/12/2005<br>carol : 10/18/2004<br>carol : 10/18/2004<br>alopez : 12/15/2003<br>mgross : 11/5/2003<br>alopez : 10/17/2003<br>alopez : 6/3/2003<br>alopez : 5/2/2003<br>terry : 5/1/2003<br>alopez : 1/31/2003<br>terry : 1/30/2003<br>alopez : 1/30/2003<br>mgross : 1/16/2003<br>alopez : 11/4/2002<br>mgross : 10/11/2002<br>alopez : 10/24/2001<br>mgross : 7/26/2001<br>mgross : 7/18/2001<br>mgross : 7/18/2001<br>alopez : 6/15/2001<br>mgross : 4/4/2001<br>mgross : 4/4/2001<br>mgross : 2/21/2001<br>terry : 2/21/2001<br>mgross : 11/2/2000<br>mgross : 7/5/2000<br>mgross : 3/6/2000<br>psherman : 1/11/2000<br>mcapotos : 1/7/2000<br>mcapotos : 1/4/2000<br>terry : 12/22/1999<br>jlewis : 8/5/1999<br>jlewis : 8/5/1999<br>terry : 7/22/1999<br>kayiaros : 7/13/1999<br>mgross : 6/4/1999<br>mgross : 5/27/1999<br>terry : 5/20/1999<br>alopez : 12/15/1998<br>alopez : 12/15/1998<br>carol : 11/10/1998<br>dholmes : 6/4/1998<br>dholmes : 6/4/1998<br>dholmes : 5/21/1998<br>dholmes : 5/21/1998<br>dholmes : 4/16/1998<br>mark : 8/25/1997<br>terry : 8/22/1997<br>mark : 4/22/1996<br>terry : 4/26/1994<br>carol : 7/21/1992<br>supermim : 3/16/1992<br>carol : 5/16/1991<br>supermim : 3/20/1990
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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">
|
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<strong>*</strong> 123890
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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CYTOTOXIC T LYMPHOCYTE-ASSOCIATED 4; CTLA4
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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CD152
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<p>
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<span class="mim-font">
|
|
Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
|
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<span class="h3 mim-font">
|
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CYTOTOXIC T LYMPHOCYTE-ASSOCIATED 4, SOLUBLE ISOFORM, INCLUDED
|
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: CTLA4</em></strong>
|
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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|
<strong>SNOMEDCT:</strong> 1197361002;
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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">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: 2q33.2
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 2:203,867,771-203,873,965 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
|
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</p>
|
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</div>
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<div>
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<br />
|
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</div>
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<div>
|
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<h4>
|
|
<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="5">
|
|
<span class="mim-font">
|
|
2q33.2
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Celiac disease, susceptibility to, 3}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
609755
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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</tr>
|
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|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Diabetes mellitus, insulin-dependent, 12}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
601388
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
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</tr>
|
|
|
|
|
|
|
|
<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
{Hashimoto thyroiditis}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
140300
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Systemic lupus erythematosus, susceptibility to}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
152700
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
616100
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
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|
</div>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
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|
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|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>CTLA4 is a member of the immunoglobulin superfamily and is a costimulatory molecule expressed by activated T cells. CTLA4 is similar to the T-cell costimulatory CD28 (186760), and both molecules bind to B7-1 (CD80; 112203) and B7-2 (CD86; 601020) on antigen-presenting cells. CTLA4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal (Magistrelli et al., 1999). </p>
|
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</span>
|
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<div>
|
|
<br />
|
|
</div>
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|
|
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|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</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>Dariavach et al. (1988) used a mouse Ctla4 probe to isolate a partial sequence for the human CTLA4 gene from a genomic cDNA library. The predicted protein shares 76% overall homology and complete identity in the cytoplasmic domain with the mouse protein. </p><p>Harper et al. (1991) isolated several cDNA clones corresponding to the human CTLA4 gene from a stimulated peripheral blood cell human cDNA library. The putative protein contains a leader sequence, a V domain, a transmembrane domain, and a cytoplasmic tail encoded by 4 exons, respectively. The cytoplasmic tail contains 2 potential phosphorylation sites. Northern blot analysis detected 2 CTLA4 mRNA transcripts of 1.8 and 0.8 kb in activated peripheral blood T cells. </p><p>Linsley et al. (1995) demonstrated that the CTLA4 protein is a homodimer interconnected by a disulfide bond in the extracellular domain at cysteine residue 120. Each monomeric polypeptide contains a high affinity binding site for the costimulatory molecules B7-1 and B7-2. </p><p>Ling et al. (1999) reported the complete revised sequence of the human and mouse CTLA4 genes. The deduced 223-amino acid human protein shows high homology to the mouse protein. There are also similarities in noncoding regions, suggesting conserved transcriptional control. Northern blot analysis detected multiple human transcripts of 1, 2.4, 5, and 7 kb at high levels in spleen, thymus, and peripheral blood leukocytes; lesser expression of the 2.4- and 5-kb transcripts was detected in multiple tissues, including testis, uterus, colon, heart, and brain. The authors suggested that the signals in organ tissues may reflect passenger lymphocytes. </p><p>Using RT-PCR, Magistrelli et al. (1999) found that nonactivated human peripheral blood T lymphocytes expressed an alternatively spliced form of CTLA4. The splicing induces deletion of the transmembrane region encoded by exon 2, resulting in the production of a soluble form of the protein with a molecular mass of 23 kD; membrane CTLA4 has an apparent molecular mass of 45 kD, suggesting that the soluble form is a monomeric protein. Functional studies showed that the soluble form of CTLA4 is downregulated by T-cell activation, in contrast to membrane CTLA4, which is upregulated by T-cell activation. The authors found the soluble form of CTLA4 in sera from 14 of 64 healthy subjects. </p><p>Oaks et al. (2000) reported that the 137-amino acid CTLA4 variant, which they called sCTLA4 (soluble CTLA4), has the same sequence as the extracellular portion of the full-length molecule (CTLA4-TM), but contains only 22 of its 34 cytoplasmic residues. RT-PCR analysis of rat tissues detected both forms of CTLA4 in lymph node, spleen, and peripheral blood, only CTLA4-TM in adult thymus, only sCTLA4 in bone marrow cells, and neither form in nonlymphoid tissues. Within T-cell subsets, equivalent amounts of both forms were detected in CD4+ (186940) cells, but CTLA4-TM was 2.5-fold greater in CD8+ T cells. </p><p>By flow cytometric analysis, Kaufmann et al. (2007) showed that CTLA4 expression was selectively upregulated in human immunodeficiency virus-1 (HIV-1; see 609423)-specific CD4-positive T cells, but not in CD8-positive T cells or control cytomegalovirus-specific CD4-positive T cells, in all categories of HIV-infected subjects tested except those with extremely low viral loads in the absence of antiretroviral therapy (elite controllers). CTLA4 expression correlated positively with disease progression and negatively with the capacity of CD4-positive T cells to express IL2 (147680). Nearly all HIV-specific CD4-positive T cells from patients with progressive disease coexpressed CTLA4 with PD1 (PDCD1; 600244), whereas just over half of HIV-specific CD4-positive T cells from elite controllers did so. Blockade of CTLA4 expression in vitro augmented HIV-specific CD4-positive T-cell function. Kaufmann et al. (2007) proposed that this reversible immunoregulatory pathway, which is selectively associated with CD4-positive T-cell dysfunction, may be an immunotherapeutic target. </p>
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<strong>Gene Structure</strong>
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<p>Harper et al. (1991) and Ling et al. (1999) determined that the CTLA4 gene contains 4 exons. </p>
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<strong>Mapping</strong>
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<p>Dariavach et al. (1988) reported that human CTLA4 maps to chromosome 2q33. By study of yeast artificial chromosomes, Buonavista et al. (1992) demonstrated that the human CD28 (186760) and CTLA4 genes are in the same fragment, indicating that they are separated by only 25 to 150 kb; a CpG island was found between these genes. </p><p>Harper et al. (1991) mapped the mouse Ctla4 gene to chromosome 1 by in situ hybridization. By means of intersubspecific backcrosses, Howard et al. (1991) demonstrated that mouse Ctla4 is located in the proximal part of chromosome 1. It is closely linked to Cd28; no recombinations were detected in 114 meiotic events examined. The authors noted that Cd28 and Ctla4 are related members of the Ig supergene family. </p>
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<strong>Biochemical Features</strong>
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<p><strong><em>Crystal Structure</em></strong></p><p>
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CTLA4 binds to the B7 isoforms with an affinity that is 10 to 100 times that of CD28. Ostrov et al. (2000) determined the crystal structure of the extracellular portion of murine Ctla4 at 2.0-angstrom resolution. Consistent with its membership in the Ig superfamily, Ctla4 displays a strand topology similar to V-alpha domains. Ctla4 has an unusual dimerization mode that places the B7 binding sites distal to the dimerization interface, allowing each Ctla4 dimer to bind 2 divalent B7 molecules. The authors suggested that periodic rearrangement of these components might explain the role of CTLA4 in the regulation of T-cell responsiveness. </p><p>Stamper et al. (2001) reported the crystal structure of the human CTLA4/B7.1 costimulatory complex at 3.0-angstrom resolution. They stated that the relatively small binding complex exhibits an unusually high degree of shape complementarity. </p><p>Schwartz et al. (2001) reported the crystal structure of the complex between the disulfide-linked homodimer of human CTLA4 and the receptor-binding domain of human B7-2 at 3.2-angstrom resolution. </p>
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<strong>Gene Function</strong>
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<p>Oaks et al. (2000) found that activation of human lymphocytes resulted in the disappearance of sCTLA4 at 48 hours followed by its gradual reappearance, whereas CTLA4-TM rapidly increased and remained present at the same level after activation. </p><p>Oaks and Hallett (2000) identified sCTLA4 in only 1 of 30 normal subjects but in 11 of 20 patients with autoimmune thyroiditis (8 of 17 with Graves disease (275000) and 3 of 3 with Hashimoto disease (140300)). The data indicated that sCTLA4 represents an intact functional receptor for CD80 (112203). </p><p>CTLA4Ig is a soluble chimeric protein consisting of the extracellular domain of human CTLA4 and a fragment of the Fc portion of human IgG1 (147100). It binds to B7-1 and to B7-2 molecules on antigen-presenting cells (APCs) and thereby blocks the CD28-mediated costimulatory signal for T-cell activation. Biologic activity of CTLA4Ig was demonstrated in a variety of animal models of transplantation (Sayegh and Turka, 1998) and autoimmunity (Reiser and Stadecker, 1996). In 43 patients with stable psoriasis vulgaris (177900), Abrams et al. (1999) administered 4 infusions of CTLA4Ig. A 50% or greater sustained improvement in clinical disease activity was achieved in 46% of patients, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. There was no markedly increased rate of intralesional T-cell apoptosis, suggesting that the decreased number of lesional T cells was probably attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. The findings illustrated the importance of the CD28/CTLA4 pathway in the pathogenesis of psoriasis and suggested a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases. </p><p>Grohmann et al. (2002) noted that Ctla4-Ig fusion protein blocked allograft and xenograft rejection in models of cardiac, liver, and pancreatic islet transplantation, but that B7 expression was required in cardiac donor cells. They hypothesized that, after binding, both Ctla4 and B7 are activated, changing the functional state of both the T cell and the antigen-presenting cell. Grohmann et al. (2002) found that in the presence of the indoleamine 2,3-dioxygenase (IDO; 147435) inhibitor, 1-methyltryptophan (1MT), Ctla4-Ig was unable to promote engraftment of islet cells in mice. In vitro, Ctla4Ig treatment resulted in an increased rate of tryptophan degradation to kynurenine to an extent similar to that induced by gamma-interferon (IFNG; 147570) and required the presence of B7 molecules on dendritic cells (DCs). Indeed, DCs expressing B7 produced enhanced levels of Ifng, but not Tnf, in response to Ctla4 ligation. Expression of both Ifng and Stat1 (600555) was required for kynurenine production and Ctla4 suppression of the rejection response, suggesting that Ifng can act on tolerogenic DCs in an autocrine or paracrine manner. </p><p>CD4 (186940)-positive/CD25 (147730)-positive regulatory T cells (Tregs) exert control over the immune response by interacting with APCs, particularly DCs. Fallarino et al. (2003) showed that mouse Cd4+/Cd25+ Tregs expressing Ctla4 conditioned B7-expressing DCs to express Ido and produce Ifng. DCs conditioned in vitro by Tregs mediated suppressive effects in vivo that were dependent on effective tryptophan catabolism. The requirement for Ctla4 expression was overcome in Tregs stimulated with lipopolysaccharide to produce substantial amounts of Ifng and interleukin-10 (IL10; 124092). Fallarino et al. (2003) concluded that Tregs prime DCs for tolerance induction through IDO-based immunoregulation. </p><p>Using in vitro migration assays and in vivo 2-photon laser scanning microscopy, Schneider et al. (2006) showed that CTLA4 increases T-cell motility and overrides the T-cell receptor (TCR)-induced stop signal required for stable conjugate formation between T cells and antigen-presenting cells. This event led to reduced contact periods between T cells and antigen-presenting cells that in turn decreased cytokine production and proliferation. Schneider et al. (2006) concluded that their results suggested a fundamentally different model of reverse stop signaling, by which CTLA4 modulates the threshold for T-cell activation and protects against autoimmunity. </p><p>CTLA4 shares 2 ligands, CD80 and CD86 (601020), with a stimulatory receptor, CD28 (186760). Qureshi et al. (2011) showed that CTLA4 can capture its ligands and CD86 from opposing cells by a process of trans-endocytosis. After removal, these costimulatory ligands are degraded inside CTLA4-expressing cells, resulting in impaired costimulation via CD28. Acquisition of CD86 from antigen-presenting cells is stimulated by T cell receptor engagement and observed in vitro and in vivo. Qureshi et al. (2011) concluded that their data revealed a mechanism of immune regulation in which CTLA4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands, accounting for many of the features of the CD28-CTLA4 system. </p><p>Chain et al. (2013) examined blood and bronchoalveolar lavage cells from individuals with chronic beryllium disease (CBD) and detected increased CTLA4 expression on CD4-positive T cells in lung compared with blood. CTLA4 expression was highest in beryllium-responsive CD4-positive T cells that retained proliferative ability and that expressed IL2. Induction of CTLA4 signaling in blood cells inhibited beryllium-induced T-cell proliferation, but it had no effect on the ability of lung cells to respond to beryllium. Chain et al. (2013) concluded that loss of CD28 on beryllium-responsive CD4-positive T cells and the resultant ineffective CTLA4 pathway in lung contribute to persistent inflammation in CBD. </p><p>Lo et al. (2015) found that LRBA (606453) regulates CTLA4 expression. LRBA colocalizes with CTLA4 in endosomal vesicles, and LRBA deficiency or knockdown increased CTLA4 turnover, which resulted in reduced levels of CTLA4 protein in FOXP3+ regulatory and activated conventional T cells. In LRBA-deficient cells, inhibition of lysosome degradation with chloroquine prevented CTLA4 loss. Lo et al. (2015) concluded that their observations elucidated a mechanism for CTLA4 trafficking and control of immune responses and suggested therapies for diseases involving the CTLA4 pathway. </p><p>Vetizou et al. (2015) found that the antitumor effects of CTLA4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA4 blockade. </p>
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<strong>Molecular Genetics</strong>
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<p>Nistico et al. (1996) identified a 49A-G transition polymorphism in exon 1 of the CTLA4 gene, resulting in a thr17-to-ala (T17A; 123890.0001) substitution in the leader peptide of the protein. Among 529 Belgian control individuals, the frequencies for the 49A and 49G alleles were 68% and 32%, respectively. </p><p>Ueda et al. (2003) identified a series of single-nucleotide polymorphisms (SNPs) between 0.2 and 6.3 kb 3-prime of the end of the CTLA4 transcript. They found that one, termed CT60 (123890.0002), encodes either a protective A/A genotype or a predisposing G/G genotype for autoimmune disease. </p><p>Zhernakova et al. (2005) tested CTLA4 gene polymorphisms for association in 350 Dutch patients with type 1 diabetes (T1D12; 601388), 310 with celiac disease (see 609755), 520 with rheumatoid arthritis (see 180300), and 900 controls. They found a significant association between so-called CTLA4 haplotype 2 and type 1 diabetes, and between CTLA4 haplotype 3 and early-onset celiac disease, but no association between CTLA4 haplotype and rheumatoid arthritis. </p><p>For discussion of a possible association between variation in the CTLA4 gene and susceptibility to rheumatoid arthritis, see 180300.</p><p><strong><em>Type 1 Diabetes Mellitus 12</em></strong></p><p>
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Nistico et al. (1996) and Marron et al. (1997) found increased transmission of the G allele of a 49A-G polymorphism (123890.0001) in several populations with insulin-dependent diabetes mellitus that mapped to chromosome 2q33 (T1D12; 601388). </p><p>Lohmueller et al. (2003) performed a metaanalysis of 301 published studies of 25 different reported associations between genetic variants and common diseases. For 8 of the 25 associations, pooled analysis of follow-up studies yielded statistically significant replication of the first report, with modest estimated genetic effects. One of these 8 associations was that between CTLA4 and type 1 diabetes, as first reported by Nistico et al. (1996). </p><p><strong><em>Graves Disease</em></strong></p><p>
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Heward et al. (1999) studied the A/G polymorphism of the CTLA4 gene in a case-control (743 individuals) and family-based (179 families) dataset of Caucasian subjects with Graves disease (275000). An increase in frequency of the G (alanine) allele was seen in patients with Graves disease compared with control subjects (42% vs 31.5%, respectively; corrected p less than 0.0002; odds ratio of 1.58). A significant difference in the distribution of GG, GA, and AA genotypes was observed between the groups (chi-square of 21.7; corrected P less than 0.00003). Increased transmission of the G allele was seen from heterozygous parents to affected offspring compared to unaffected offspring (chi-square of 5.7; p = 0.025). Circulating free T4 concentrations at diagnosis were significantly associated with CTLA4 genotype (F = 3.26; p of 0.04). These results supported the hypothesis that CTLA4 may play a role in regulating self-tolerance by the immune system and in the pathogenesis of autoimmune disorders such as Graves disease. </p><p>Kouki et al. (2000) reported that there are more Graves disease patients with G/G or A/G alleles at nucleotide 49 of the CTLA4 gene and significantly fewer with the A/A allele compared with normal controls. Flow cytometric analysis failed to detect any differences in intracellular or surface expression of CTLA4 in Graves disease or Hashimoto thyroiditis patients compared with normal controls. T-cell proliferation in response to Epstein Barr virus-transformed B cells was significantly greater in subjects with the G/G allele than in those with the A/A allele. Incubation of anti-CTLA4 monoclonal antibody with peripheral blood mononuclear cells showed that individuals with the G/G allele had significantly less augmentation of the T-cell proliferative response than did individuals with the A/A allele. Kouki et al. (2000) concluded that the CTLA4 polymorphism affects the inhibitory function of the molecule and that the G allele is associated with reduced control of T-cell proliferation, thereby contributing to the pathogenesis of Graves disease and other autoimmune diseases. </p><p>Ueda et al. (2003) did not find an association between the 49A-G polymorphism and Graves disease. </p><p>Smoking and demographic variables are known to be risk factors for the development of thyroid-associated orbitopathy (TAO) among patients with Graves hyperthyroidism. Vaidya et al. (1999) showed that the presence and severity of TAO are associated with a specific allele of the CTLA4 gene. In addition to the demonstrated linkage and association of the CTLA4 locus with both type I diabetes (T1D12; 601388) and Graves disease, Vaidya et al. (1999) presented evidence that the biallelic polymorphism (A/G) at codon 17 of the CTLA4 gene also conferred susceptibility to TAO. They showed that the G-carrying genotypes of CTLA4 (AG and GG) were associated with an increased risk of TAO, and that this was independent of sex, smoking status, or previous radioiodine administration. </p><p>Wang et al. (2004) showed an association between the 49G allele and early relapse of Graves disease following discontinuation of drug treatment. In a follow-up study of an additional 60 patients with GRD, Wang et al. (2007) found by multivariate logistic regression analysis that the GG genotype had an adjusted odds ratio of 2.2 (95% CI, 1.1-4.4) compared with the combined group of GA plus AA. Other significant predictors of relapse were large goiter size at the end of treatment and positive TSH-binding inhibitory Ig at the end of treatment. </p><p>The production of high titers of autoantibodies against thyroglobulin (188450) and thyroid peroxidase (606765) is a hallmark of autoimmune thyroid diseases. To identify susceptibility genes for the production of thyroid antibodies, Tomer et al. (2001) performed a genomewide scan in 56 multiplex families (323 individuals) in which all family members with autoimmune thyroid diseases and/or detectable thyroid antibodies were considered affected. The highest 2-point lod score of 3.6 was obtained for marker D2S325 on chromosome 2q33 at 210.9 cM. This locus showed no evidence for linkage to Graves disease or Hashimoto thyroiditis (2-point lod scores, 0.42 for Graves disease and -0.60 for Hashimoto thyroiditis), demonstrating that the gene in this region conferred susceptibility to thyroid antibodies, but that clinical disease development required additional genetic and/or environmental factors. Multipoint linkage analysis for thyroid antibodies using additional markers yielded a maximum lod score of 4.2 for marker D2S155 at 209.8 cM (with heterogeneity, alpha = 0.41). There was a significantly increased frequency of the 49G allele in probands of the linked families compared with probands of the unlinked families or with controls. Tomer et al. (2001) concluded that the major gene for thyroid antibody production on chromosome 2q33 was the CTLA4 gene, which contributed to the genetic susceptibility to thyroid antibody production, but that there was no evidence that it contributed specifically to Graves or Hashimoto diseases. </p><p>To investigate an association between the 49A/G polymorphism of the CTLA4 gene and remission of Graves disease during antithyroid drug treatment, Kinjo et al. (2002) studied this polymorphism in 144 Japanese Graves disease patients treated with antithyroid drugs. A significant increase in the frequency of the G allele was seen in patients compared with controls (p = 0.0095). The patients were divided into 3 groups according to time of disappearance of TSH receptor antibody (TRAb) after the start of treatment. In group A patients, TRAb had disappeared within 1 year after the start of treatment; in group B, TRAb had disappeared between the beginning of the second year and the end of the fifth year of treatment; and in group C, TRAb continued to be positive after 5 years of treatment. The frequencies of the GG genotype and the G allele were significantly higher in group C patients with persistently positive TRAb over 5 years of treatment than in the other groups (p less than 0.0001). Group C patients did not have the AA genotype. The periods of time until remission were significantly shorter in the AA genotype. The authors concluded that Graves disease patients with the G allele need to continue antithyroid drug treatment for longer periods. </p><p>Wang et al. (2004) tested whether the G allele of the 49A/G SNP in the CTLA4 gene, associated with higher risk of developing Graves disease, was associated with early relapse of the disease after drug withdrawal in 148 Chinese patients with Graves disease and 171 controls. The G/G genotype had a 79% frequency in patients who experienced relapse within 9 months compared to 39% in patients who relapsed 3 or more years after discontinuation of treatment. At the end of treatment, the percentage of patients with persistent TSH receptor (TSHR; 603372) antibody was statistically different (A/A, 9.0%; A/G, 20.8%; G/G, 45.5%; p = 0.004). The authors concluded that the A/G polymorphism of the CTLA4 gene affects the progress of GD and that the G/G genotype is associated with poor outcome. They also noted that patients with the G/G genotype may not be candidates for antithyroid drugs. </p><p>Kavvoura et al. (2007) performed a metaanalysis examining the association of the CTLA4 49A-G and CT60 polymorphisms with increased susceptibility to Graves disease (GRD; see 275000) and/or Hashimoto thyroiditis (HT; see 140300), which included group-level data from more than 13,000 subjects and individual-level data from more than 5,000 subjects. The group-level data showed highly significant associations of both GRD and HT with each polymorphism separately, with p values in the range of 10(-3) and 10(-16) in the main analysis. The individual-level data allowed the consideration of haplotypes, including both polymorphisms. Kavvoura et al. (2007) found that the association with the 49A-G polymorphism was probably mostly the result of linkage disequilibrium with CT60. The G allele of the CT60 polymorphism increased the odds of both GRD and HT by 1.4-fold. A dose-effect association was also demonstrated, as the presence of 2 copies of the susceptible haplotype GG almost doubled the odds compared with 1 copy of GG. </p><p>Chu et al. (2011) conducted a genomewide association study in 1,536 individuals with Graves disease and 1,516 controls, and then evaluated a group of associated SNPs in a second set of 3,994 cases and 3,510 controls. Chu et al. (2011) confirmed the association with rs1024161 at CTLA4; T is the risk allele (combined odds ratio = 1.30; 95% CI 1.23-1.38; p = 2.34 x 10(-17)). </p><p><strong><em>Other Endocrine Autoimmune Diseases</em></strong></p><p>
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Donner et al. (1997) found an association between Hashimoto thyroiditis (140300) and the 49G allele. Although patients with Addison disease (240200) did not differ significantly from controls with regard to the 49G-A polymorphism, those patients carrying the susceptibility marker, human leukocyte antigen DQA1*0501, had a significantly higher frequency of the G allele compared to controls with the same DQA1 allele (P less than 0.05). Donner et al. (1997) concluded that the 49G (ala17) allele of the CTLA4 gene confers genetic susceptibility to Hashimoto thyroiditis and to Addison disease in individuals who also carry DQA1*0501+. </p><p><strong><em>Celiac Disease</em></strong></p><p>
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Djilali-Saiah et al. (1998) found a significantly increased frequency of the 49A allele in 101 French Caucasian patients with celiac disease (CELIAC3; 609755) compared to controls (82.2% vs 65.8%, p less than 0.0001), reflecting the increased frequency of A/A homozygotes among patients compared with controls (68.3% vs 47.7%, p = 0.002). The effect remained after stratification of patients according to their DR-DQ phenotype. The authors concluded that the A allele of the CTLA4 position 49 polymorphism conferred an HLA-independent predisposition to celiac disease. </p><p>Naluai et al. (2000) analyzed the 49A/G polymorphism (123890.0001) in 107 Swedish and Norwegian families with celiac disease and found a significant association, with preferential transmission of the 49A allele by the transmission disequilibrium test (p less than 0.007). Nonparametric linkage analysis yielded a score of 2.1 (p = 0.018), suggesting that the CTLA4 region is a susceptibility region in celiac disease. Naluai et al. (2000) noted that, of several chronic inflammatory diseases exhibiting associations to the CTLA4 49A/G polymorphism, celiac disease is the only one associated with the A allele, suggesting that the 49A/G alleles of CTLA4 are in linkage disequilibrium with 2 distinct disease-predisposing alleles with separate effects. </p><p>Van Belzen et al. (2004) genotyped 215 Dutch celiac patients and 213 controls for the 49A-G and CT60 (123890.0002) polymorphisms in the CTLA4 gene. They found no significant difference between patients and controls in the frequency of the 49G allele, but did find an increase in the frequency of the CT60 G allele in patients (p = 0.048). Van Belzen et al. (2004) concluded that CTLA4 is involved in the development of celiac disease. </p><p>Hunt et al. (2005) pointed out that 5 linkage studies had individually provided nominally significant evidence for a celiac disease susceptibility locus on chromosome 2q (2q33), making CTLA4 a promising candidate gene. They genotyped CTLA4 variants to tag all common haplotypes (more than 5% frequency) and a variant of inducible costimulator (ICOS; 604558), which also maps to 2q33, in 340 white U.K. celiac disease cases and in a group of healthy controls. A common CTLA4 haplotype showed strong association with celiac disease and contained multiple alleles reported to affect immunologic function. Hunt et al. (2005) suggested that loss of tolerance to dietary antigens in celiac disease may be mediated in part by heritable variants in cosignaling genes regulating T-cell responses. </p><p><strong><em>Systemic Lupus Erythematosus</em></strong></p><p>
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Hudson et al. (2002) investigated association between systemic lupus erythematosus (SLE; 152700) and SNPs of the CTLA4 gene. The genotypes at position -1722(T/C) were significantly associated with SLE. The frequency of T/T homozygotes was higher in patients than in controls; conversely, the frequency of C/C homozygotes and C/T heterozygotes were higher in controls than in patients. </p><p>In a metaanalysis of 7 published studies and their own study, Barreto et al. (2004) examined the association between the 49A-G SNP in exon 1 of the CTLA4 gene and SLE. The authors found that individuals with the GG genotype were at significantly higher risk of developing SLE; carriers of the A allele had a significantly lower risk of developing the disease, and the AA genotype acted as a protective genotype for SLE. </p><p><strong><em>Hepatitis B Virus Clearance and Persistence</em></strong></p><p>
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Thio et al. (2004) genotyped 6 SNPs in CTLA4 in a large cohort of individuals with either hepatitis B virus (HBV; see 610424) clearance or persistence. They found that the wildtype haplotype, which contains -1722T and +49A, was associated with viral persistence. In contrast, haplotypes containing +49G either alone or with -1722C were associated with viral clearance. The association with viral clearance was stronger for individuals homozygous for +49G. Thio et al. (2004) concluded that genes important in immune system counterregulation are also important in recovery from chronic viral illness. </p><p><strong><em>Immune Dysregulation with Autoimmunity, Immunodeficiency, and Lymphoproliferation</em></strong></p><p>
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In 6 patients from 4 families with immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL; 616100), Kuehn et al. (2014) identified 4 different heterozygous loss-of-function mutations in the CTLA4 gene (see, e.g., 123890.0003-123890.0005). Patients had decreased numbers of circulating naive CD45RA+ T cells compared to controls, as well as progressive loss of circulating B cells. Patient regulatory T cells showed decreased FOXP3 (300292) and IL2RA (147730) expression, and these cells poorly suppressed the proliferation of cocultured T responder cells in vitro. Knockdown of CTLA4 using siRNA in control mononuclear cells recapitulated the hyperproliferative T-cell phenotype. Patients had increased frequency of autoreactive CD21(lo) B cells, which are considered anergic or exhausted, and these cells showed increased tendency for apoptosis as well as decreased ability to secrete immunoglobulin. These changes resulted in B-cell lymphopenia and were believed to be a result of regulatory T-cell dysfunction. The findings demonstrated that full expression of CTLA4 is required to govern T- and B-cell lymphocyte homeostasis, and that reduction of CTLA4 expression contributes to loss of immune tolerance and causes infiltrative autoimmune disease. </p><p>In 11 patients from 6 unrelated families with IDAIL, Schubert et al. (2014) identified 6 different heterozygous mutations in the CTLA4 gene (see, e.g., 123890.0006-123890.0008). The mutation in the first family was found by whole-exome sequencing; mutations in subsequent families were found by direct screening of the CTLA4 gene in 71 unrelated probands with common variable immunodeficiency (CVID) and enteropathy or autoimmunity. Patient regulatory T cells showed decreased CTLA4 protein expression. In vitro studies showed impaired suppressive function of regulatory T cells and impaired ligand capture and transendocytosis of CD80 (112203). </p>
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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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</h4>
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<span class="mim-text-font">
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<p>CTLA4 has a role in T-cell activation and shares significant sequence identity with CD28; the 2 mouse proteins are 76% alike. Whereas CD28 is found on the membrane of resting T cells, CTLA4 is detectable only on cells activated after antigen presentation. Both molecules bind to the same ligands. Waterhouse et al. (1995) showed that homozygous Ctla4 gene-targeted mice accumulated T-cell blasts in their lymph nodes and spleens, which were enlarged 5 to 10 times normal. In contrast, CD28-homozygous knockout mice had diminished T-cell responses (Shahinian et al., 1993). Waterhouse et al. (1995) found that Ctla4-deficient mice had much higher serum immunoglobin concentrations than normal, that their B cells exhibited activation markers, and that many of their tissues showed extensive lymphocyte proliferation. The Ctla4-knockout mice became moribund by 3 to 4 weeks of age and died of apparent myocardial failure due to lymphocytic infiltration. Although CTLA4-deficient T cells proliferated spontaneously and strongly when stimulated through the T-cell receptor, they were sensitive to cell death induced by cross-linking of the Fas receptor and by gamma irradiation. Through these and other findings, the authors concluded that CTLA4 plays an important inhibitory role in regulating lymphocyte expansion. Allison and Krummel (1995) reviewed the current literature on T-cell costimulation in light of the findings by Waterhouse et al. (1995). </p><p>Mice deficient in either Jak3 (600173) or Ctla4 have similar predominantly CD4-positive peripheral T-cell phenotypes, but die from SCID and lymphoproliferative disorder, respectively. Gozalo-Sanmillan et al. (2001) used CDR3 spectratyping analysis of T-cell receptor repertoires of Jak3- and Ctla4-deficient mice. Ctla4 -/- mice had the same diverse repertoire as control unimmunized mice, whereas Jak3 -/- peripheral but not thymic T cells had a limited number of expanded T-cell clones, suggesting an antigen-dependent activation in the Jak3-deficient mice as opposed to a universal activation in the Ctla4-deficient mice. The authors concluded that the 2 similar phenotypes of T-cell expansion are derived by distinct mechanisms. </p><p>Bour-Jordan et al. (2003) showed that T cells from double-knockout mice deficient in Ctla4 and Stat6 (601512) were skewed toward a Th2 phenotype in vitro and in vivo by bypassing the need for Stat6. Instead, induction of Gata3 (131320) occurred in vitro and Cd4-positive cells migrated to peripheral tissues in vivo. In addition, T-cell receptor crosslinking induced a relative increase of Nfatc1 (600489) versus Nfatc2 (600490) nuclear translocation and enhanced NFKB (164011) activation compared with Stat6 -/- T cells. Bour-Jordan et al. (2003) proposed that CTLA4 regulates T-cell differentiation by controlling the overall strength of the T-cell activation signal, bypassing the cytokine dependency of Th2 differentiation. </p><p>Wing et al. (2008) found that conditional deletion of Ctla4 in Foxp3 (300292)-positive Tregs resulted in spontaneous development of systemic lymphoproliferation, fatal T cell-mediated autoimmune disease, and hyper-IgE production in mice 7 weeks after birth. Reconstitution of mice with Ctla4 -/- Tregs halted tumor growth and enhanced survival. Flow cytometric analysis showed no alteration in thymic selection of Tregs, but there was a change in expression of Cd80 (112203) and Cd86 (601020) in peripheral DCs. Wing et al. (2008) proposed that natural Tregs may require CTLA4 to suppress immune responses by affecting the potency of APCs to activate other T cells. </p><p>Vom Berg et al. (2013) used a syngeneic mouse model for glioblastoma (GB; see 137800) and administered cytokines in the tumor area to overcome the immunosuppressive GB microenvironment. The authors found that Il12 (see 161561), but not Il23 (see 605580), reversed GB-induced immunosuppression and led to tumor clearance in a T cell-dependent manner. To better replicate the human clinical situation, vom Berg et al. (2013) delayed therapy until after GB progression. They found that intratumoral application of Il12 combined with systemic anti-Ctla4, but not monotherapy with either Il12 or anti-Ctla4, led to tumor eradication even at advanced disease stages. The Il12 and anti-Ctla4 combination treatment acted predominantly on Cd4-positive T cells, causing a drastic reduction in Foxp3-positive Tregs and an increase in effector T cells. Vom Berg et al. (2013) proposed that the combination of intratumoral IL12 and anti-CTLA4 should be tested in clinical trials for treatment of GB and, possibly, other solid tumors. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>8 Selected Examples):</strong>
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</h4>
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<p />
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 HASHIMOTO THYROIDITIS, SUSCEPTIBILITY TO</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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THYROID-ASSOCIATED ORBITOPATHY, SUSCEPTIBILITY TO, INCLUDED<br />
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SYSTEMIC LUPUS ERYTHEMATOSUS, SUSCEPTIBILITY TO, INCLUDED<br />
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TYPE 1 DIABETES MELLITUS 12, SUSCEPTIBILITY TO, INCLUDED<br />
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CELIAC DISEASE, SUSCEPTIBILITY TO, 3, INCLUDED
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</span>
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<span class="mim-text-font">
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CTLA4, 49A-G, THR17ALA
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<br />
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SNP: rs231775,
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gnomAD: rs231775,
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ClinVar: RCV000018423, RCV000018424, RCV000018425, RCV000018427, RCV000455037, RCV001255201, RCV001517779, RCV001723578
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<span class="mim-text-font">
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<p>Nistico et al. (1996) identified a 49A-G transition polymorphism in exon 1 of the CTLA4 gene, resulting in a thr17-to-ala (T17A) substitution. Among 529 Belgian control individuals, the frequencies for the 49A and 49G alleles were 68% and 32%, respectively. </p><p>In 48 Italian families in which at least 2 sibs were affected with type 1 diabetes mellitus (T1D12; 601388), Nistico et al. (1996) found evidence for preferential transmission of the 49G allele to affected offspring. Similar findings were obtained for 44 Spanish IDDM families, but not for families from the United Kingdom, Sardinia, or the US. Marron et al. (1997) found highly significant transmission of the 49G allele in patients with IDDM in 3 Mediterranean European populations (Italian, Spanish, and French), a Mexican American population, and Korean population. However, significant heterogeneity was observed; datasets of British, Sardinian, and Chinese populations did not show any deviation for the A/G polymorphism, whereas the Caucasian American dataset showed a weak transmission deviation. The results suggested that a true IDDM susceptibility locus is located near CTLA4. </p><p>Donner et al. (1997) found that patients with Hashimoto thyroiditis (140300) had a significantly higher number of the 49G allele compared to controls, both as homozygotes (22% vs 15%) and heterozygotes (53% vs 46%), and less of the A allele compared to controls as homozygotes (25% vs 39%; P less than 0.04). They also found that the phenotypic frequency for the G allele was significantly higher in patients (75%), compared with controls (61%), P less than 0.03. Whereas Addison disease (240200) subjects did not differ significantly from controls, those carrying the susceptibility marker, human leukocyte antigen DQA1*0501, had a significantly higher frequency of the G allele than controls with the same DQA1 allele (P less than 0.05). Donner et al. (1997) concluded that the 49G allele (ala17) of the CTLA4 gene conferred genetic susceptibility to Hashimoto thyroiditis, whereas this finding only applied to the subgroup of patients with Addison disease carrying DQA1*0501+. </p><p>Vaidya et al. (1999) presented evidence that the alanine-17 allele also confers susceptibility to thyroid-associated orbitopathy in patients with Graves disease. </p><p>Rau et al. (2001) analyzed the CTLA4 49A/G polymorphism in 300 Caucasian patients with type 2 diabetes (125853) and 466 healthy controls. All patients were negative for glutamate decarboxylase and islet cell antibodies. The distribution of alleles and the genotypic and phenotypic frequencies were similar among patients and controls. However, analysis of clinical and biochemical parameters revealed a tendency of GG (alanine/alanine) toward younger age at disease manifestation, lower body mass index, and basal C-peptide level, as well as earlier start of insulin treatment and higher portion of patients on insulin. Patients with the AA genotype were significantly less likely to develop microangiopathic lesions. The authors concluded that CTLA4 ala17 does not represent a major risk factor for type II diabetes. </p><p>Zalloua et al. (2004) evaluated the role of the CTLA4 exon 1 A49G polymorphism as a risk factor for type 1 diabetes in the Lebanese population. The CTLA4 G allele was found to be more frequently present in patients with type 1 diabetes (32.4%) than in control individuals (24.5%). The GG genotype was also significantly higher among patients (12.6%) than in controls (4.2%). Furthermore, in HLA-DQB1*0201-positive patients with type 1 diabetes, the GG and AA genotypes were higher and lower, respectively, than those found in control individuals. </p><p>In a metaanalysis of 7 published studies and their own study, Barreto et al. (2004) examined the association between the 49A-G SNP and systemic lupus erythematosus (152700). The authors found that individuals with the GG genotype were at significantly higher risk of developing SLE; carriers of the A allele had a significantly lower risk of developing the disease, and the AA genotype acted as a protective genotype for SLE. </p><p>In a metaanalysis of 14 independent studies testing association between CTLA4 polymorphisms and SLE, Lee et al. (2005) confirmed that the 49A-G polymorphism is significantly associated with SLE susceptibility, particularly in Asians. </p><p>Djilali-Saiah et al. (1998) found a significantly increased frequency of the 49A allele in 101 French Caucasian patients with celiac disease compared to controls (82.2% vs 65.8%, p less than 0.0001), reflecting the increased frequency of A/A homozygotes among patients compared with controls (68.3% vs 47.7%, p = 0.002). The effect remained after stratification of patients according to their DR-DQ phenotype. The authors concluded that the A allele of the CTLA4 position 49 polymorphism conferred an HLA-independent predisposition to celiac disease. </p><p>Naluai et al. (2000) analyzed the 49A/G polymorphism in 107 Swedish and Norwegian families with celiac disease and found a significant association, with preferential transmission of the 49A allele by the transmission disequilibrium test (p less than 0.007). Nonparametric linkage analysis yielded a score of 2.1 (p = 0.018), suggesting that the CTLA4 region is a susceptibility region in celiac disease. Naluai et al. (2000) noted that, of several chronic inflammatory diseases exhibiting associations to the CTLA4 49A/G polymorphism, celiac disease is the only one associated with the A allele, suggesting that the 49A/G alleles of CTLA4 are in linkage disequilibrium with 2 distinct disease-predisposing alleles with separate effects. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 HASHIMOTO THYROIDITIS, SUSCEPTIBILITY TO</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CELIAC DISEASE, SUSCEPTIBILITY TO, 3, INCLUDED
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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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CTLA4, 60A-G, 3-PRIME UTR
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<br />
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SNP: rs3087243,
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gnomAD: rs3087243,
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ClinVar: RCV000018429, RCV000018430, RCV001254798, RCV001515646, RCV004707853
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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>Ueda et al. (2003) identified a series of single-nucleotide polymorphisms (SNPs) between 0.2 and 6.3 kb 3-prime of the end of the CTLA4 transcript. One was termed CT60 and encodes either a protective A/A genotype or a predisposing G/G genotype for autoimmune disease (rs3087243). CT60 is a common SNP, with 63.4% of 1,316 Graves disease (275000) patient chromosomes and 53.2% of 1,646 control chromosomes having the susceptible G allele. Compared with the protective CT60 A/A genotype, the A/G and G/G genotypes had odds ratios of 1.59 (1.19-2.13) and 2.32 (1.71-3.15), respectively. In controls, the A/A, A/G, and G/G genotypes had frequencies of 22.8%, 48.0%, and 29.2%, and in Graves disease cases, 13.7%, 45.7%, and 40.6%, respectively. Conversely, relative to the disease-predisposing G/G genotype, A/G and A/A had odds ratios of 0.68 (0.54-0.86) and 0.43 (0.32-0.59), respectively. The CT60 SNP was also associated with autoimmune hypothyroidism, or Hashimoto thyroiditis (140300) to the same degree as Graves disease (odds ratio = 1.45 (1.17-1.80); p = 0.0005). However, the effect was much weaker in type I diabetes. Ueda et al. (2003) suggested the presence of a common Graves disease, type I diabetes (T1D12; 601388), and autoimmune hypothyroidism locus in the 6.1-kb 3-prime region of CTLA4. Using a real-time PCR assay, Ueda et al. (2003) showed that the CT60 polymorphism determines the efficiency of the splicing and production of soluble CTLA4, with the CT60G disease-susceptibility haplotype producing less soluble CTLA4 transcript than the resistant CT60A haplotype. In a mouse model of type I diabetes, susceptibility was also associated with variation in CTLA4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. </p><p>Van Belzen et al. (2004) genotyped 215 Dutch patients with celiac disease (609755) and 213 controls for the 49A-G (123890.0001) and CT60 polymorphisms in the CTLA4 gene. They found no significant difference between patients and controls in the frequency of the 49G allele, but did find an increase in the frequency of the CT60 G allele in patients (p = 0.048). Van Belzen et al. (2004) concluded that CTLA4 is involved in the development of celiac disease. </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 IMMUNE DYSREGULATION WITH AUTOIMMUNITY, IMMUNODEFICIENCY, AND LYMPHOPROLIFERATION</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CTLA4, ARG51TER
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<br />
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SNP: rs606231417,
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ClinVar: RCV000148290, RCV000788671, RCV002515995, RCV005016468
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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 father and daughter with immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL; 616100), Kuehn et al. (2014) identified a heterozygous c.151C-T transition in exon 2 of the CTLA4 gene, resulting in an arg51-to-ter (R51X) substitution in the ligand-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Sequencing Project databases. Analysis of patient cells showed that the mutant mRNA was degraded, consistent with nonsense-mediated mRNA decay. </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 IMMUNE DYSREGULATION WITH AUTOIMMUNITY, IMMUNODEFICIENCY, AND LYMPHOPROLIFERATION</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CTLA4, 1-BP DEL, 75G
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<br />
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SNP: rs606231418,
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gnomAD: rs606231418,
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ClinVar: RCV000148291
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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 38-year-old man with immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL; 616100), Kuehn et al. (2014) identified a heterozygous 1-bp deletion (c.75delG) in exon 1 of the CTLA4 gene, resulting in a frameshift and premature termination (Leu28PhefsTer44). The mutation was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Sequencing Project databases. </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 IMMUNE DYSREGULATION WITH AUTOIMMUNITY, IMMUNODEFICIENCY, AND LYMPHOPROLIFERATION</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CTLA4, IVS3DS, G-C, +5
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<br />
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SNP: rs606231419,
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ClinVar: RCV000148292
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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 father and son with immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL; 616100), Kuehn et al. (2014) identified a heterozygous G-to-C transversion in intron 3 of the CTLA4 gene (c.567+5G-C), resulting in the absence of exon 3 and the production of only a soluble form of CTLA4; full-length mRNA encoding the membrane-bound form was decreased. The mutation was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Sequencing Project databases. </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 IMMUNE DYSREGULATION WITH AUTOIMMUNITY, IMMUNODEFICIENCY, AND LYMPHOPROLIFERATION</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CTLA4, CYS35TER
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<br />
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SNP: rs606231420,
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ClinVar: RCV000148293
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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 5 affected members of a large family with immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL; 616100), Schubert et al. (2014) identified a heterozygous c.105C-A transversion in exon 1 of the CTLA4 gene, resulting in a cys35-to-ter (C35X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP database. Six unaffected family members also carried the mutation, consistent with incomplete penetrance. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 IMMUNE DYSREGULATION WITH AUTOIMMUNITY, IMMUNODEFICIENCY, AND LYMPHOPROLIFERATION</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CTLA4, IVS1DS, G-T, +1
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<br />
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SNP: rs606231421,
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ClinVar: RCV000148294
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL; 616100), Schubert et al. (2014) identified a heterozygous G-to-T transversion in intron 1 of the CTLA4 gene (c.110+1G-T), resulting in disruption of a donor splice site and predicted to result in haploinsufficiency. </p>
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</span>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 IMMUNE DYSREGULATION WITH AUTOIMMUNITY, IMMUNODEFICIENCY, AND LYMPHOPROLIFERATION</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CTLA4, ARG70TRP
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<br />
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SNP: rs606231422,
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ClinVar: RCV000148295, RCV001311981
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sibs with immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL; 616100), Schubert et al. (2014) identified a heterozygous c.208C-T transition in the CTLA4 gene, resulting in an arg70-to-trp (R70W) substitution at a highly conserved residue in the extracellular domain, predicted to interfere with ligand binding. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Abrams, J. R., Lebwohl, M. G., Guzzo, C. A., Jegasothy, B. V., Goldfarb, M. T., Goffe, B. S., Menter, A., Lowe, N. J., Krueger, G., Brown, M. J., Weiner, R. S., Birkhofer, M. J., Warner, G. L., Berry, K. K., Linsley, P. S., Krueger, J. G., Ochs, H. D., Kelley, S. L., Kang, S.
|
|
<strong>CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris.</strong>
|
|
J. Clin. Invest. 103: 1243-1252, 1999.
|
|
|
|
|
|
[PubMed: 10225967]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1172/JCI5857]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Allison, J. P., Krummel, M. F.
|
|
<strong>The yin and yang of T cell costimulation.</strong>
|
|
Science 270: 932-933, 1995.
|
|
|
|
|
|
[PubMed: 7481795]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.270.5238.932]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Barreto, M., Santos, E., Ferreira, R., Fesel, C., Fontes, M. F., Pereira, C., Martins, B., Andreia, R., Viana, J. F., Crespo, F., Vasconcelos, C., Ferreira, C., Vicente, A. M.
|
|
<strong>Evidence for CTLA4 as a susceptibility gene for systemic lupus erythematosus.</strong>
|
|
Europ. J. Hum. Genet. 12: 620-626, 2004.
|
|
|
|
|
|
[PubMed: 15138458]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/sj.ejhg.5201214]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bour-Jordan, H., Grogan, J. L., Tang, Q., Auger, J. A., Locksley, R. M., Bluestone, J. A.
|
|
<strong>CTLA-4 regulates the requirement for cytokine-induced signals in T(H)2 lineage commitment.</strong>
|
|
Nature Immun. 4: 182-188, 2003.
|
|
|
|
|
|
[PubMed: 12524538]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ni884]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Buonavista, N., Balzano, C., Pontarotti, P., Le Paslier, D., Golstein, P.
|
|
<strong>Molecular linkage of the human CTLA4 and CD28 Ig-superfamily genes in yeast artificial chromosomes.</strong>
|
|
Genomics 13: 856-861, 1992.
|
|
|
|
|
|
[PubMed: 1322357]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/0888-7543(92)90169-s]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Chain, J. L., Martin, A. K., Mack, D. G., Maier, L. A., Palmer, B. E., Fontenot, A. P.
|
|
<strong>Impaired function of CTLA-4 in the lungs of patients with chronic beryllium disease contributes to persistent inflammation.</strong>
|
|
J. Immun. 191: 1648-1656, 2013.
|
|
|
|
|
|
[PubMed: 23851684]
|
|
|
|
|
|
[Full Text: https://doi.org/10.4049/jimmunol.1300282]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Chu, X., Pan, C.-M., Zhao, S.-X., Liang, J., Gao, G.-Q., Zhang, X.-M., Yuan, G.-Y., Li, C.-G., Xue, L.-Q., Shen, M., Liu, W., Xie, F., and 37 others.
|
|
<strong>A genome-wide association study identifies two new risk loci for Graves' disease.</strong>
|
|
Nature Genet. 43: 897-901, 2011.
|
|
|
|
|
|
[PubMed: 21841780]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng.898]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Dariavach, P., Mattei, M.-G., Golstein, P., Lefranc, M.-P.
|
|
<strong>Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains.</strong>
|
|
Europ. J. Immun. 18: 1901-1905, 1988.
|
|
|
|
|
|
[PubMed: 3220103]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/eji.1830181206]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Djilali-Saiah, I., Schmitz, J., Harfouch-Hammoud, E., Mougenot, J.-F., Bach, J.-F., Caillat-Zucman, S.
|
|
<strong>CTLA-4 gene polymorphism is associated with predisposition to coeliac disease.</strong>
|
|
Gut 43: 187-189, 1998.
|
|
|
|
|
|
[PubMed: 10189842]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1136/gut.43.2.187]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Donner, H., Braun, J., Seidl, C., Rau, H., Finke, R., Ventz, M., Walfish, P. G., Usadel, K. H., Badenhoop, K.
|
|
<strong>Codon 17 polymorphism of the cytotoxic T lymphocyte antigen 4 gene in Hashimoto's thyroiditis and Addison's disease.</strong>
|
|
J. Clin. Endocr. Metab. 82: 4130-4132, 1997.
|
|
|
|
|
|
[PubMed: 9398726]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1210/jcem.82.12.4406]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Fallarino, F., Grohmann, U., Hwang, K. W., Orabona, C., Vacca, C., Bianchi, R., Belladonna, M. L., Fioretti, M. C., Alegre, M.-L., Puccetti, P.
|
|
<strong>Modulation of tryptophan catabolism by regulatory T cells.</strong>
|
|
Nature Immun. 4: 1206-1212, 2003.
|
|
|
|
|
|
[PubMed: 14578884]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ni1003]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gozalo-Sanmillan, S., McNally, J. M., Lin, M. Y., Chambers, C. A., Berg, L. J.
|
|
<strong>Cutting edge: two distinct mechanisms lead to impaired T cell homeostasis in Janus kinase 3- and CTLA-4-deficient mice.</strong>
|
|
J. Immun. 166: 727-730, 2001.
|
|
|
|
|
|
[PubMed: 11145642]
|
|
|
|
|
|
[Full Text: https://doi.org/10.4049/jimmunol.166.2.727]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Grohmann, U., Orabona, C., Fallarino, F., Vacca, C., Calcinaro, F., Falorni, A., Candeloro, P., Belladonna, M. L., Bianchi, R., Fioretti, M. C., Puccetti, P.
|
|
<strong>CTLA-4-Ig regulates tryptophan catabolism in vivo.</strong>
|
|
Nature Immun. 3: 1097-1101, 2002.
|
|
|
|
|
|
[PubMed: 12368911]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ni846]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Harper, K., Balzano, C., Rouvier, E., Mattei, M.-G., Luciani, M.-F., Golstein, P.
|
|
<strong>CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location.</strong>
|
|
J. Immun. 147: 1037-1044, 1991.
|
|
|
|
|
|
[PubMed: 1713603]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Heward, J. M., Allahabadia, A., Armitage, M., Hattersley, A., Dodson, P. M., Macleod, K., Carr-Smith, J., Daykin, J., Daly, A., Sheppard, M. C., Holder, R. L., Barnett, A. H., Franklyn, J. A., Gough, S. C. L.
|
|
<strong>The development of Graves' disease and the CTLA-4 gene on chromosome 2q33.</strong>
|
|
J. Clin. Endocr. Metab. 84: 2398-2401, 1999.
|
|
|
|
|
|
[PubMed: 10404810]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1210/jcem.84.7.5820]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Howard, T. A., Rochelle, J. M., Seldin, M. F.
|
|
<strong>Cd28 and Ctla-4, two related members of the Ig supergene family, are tightly linked on proximal mouse chromosome 1.</strong>
|
|
Immunogenetics 33: 74-76, 1991.
|
|
|
|
|
|
[PubMed: 1671668]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/BF00211698]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hudson, L. L., Rocca, K., Song, Y. W., Pandey, J. P.
|
|
<strong>CTLA-4 gene polymorphisms in systemic lupus erythematosus: a highly significant association with a determinant in the promoter region.</strong>
|
|
Hum. Genet. 111: 452-455, 2002.
|
|
|
|
|
|
[PubMed: 12384790]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s00439-002-0807-2]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hunt, K. A., McGovern, D. P. B., Kumar, P. J., Ghosh, S., Travis, S. P. L., Walters, J. R. F., Jewell, D. P., Playford, R. J., van Heel, D. A.
|
|
<strong>A common CTLA4 haplotype associated with coeliac disease.</strong>
|
|
Europ. J. Hum. Genet. 13: 440-444, 2005.
|
|
|
|
|
|
[PubMed: 15657618]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/sj.ejhg.5201357]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kaufmann, D. E., Kavanagh, D. G., Pereyra, F., Zaunders, J. J., Mackey, E. W., Miura, T., Palmer, S., Brockman, M., Rathod, A., Piechocka-Trocha, A., Baker, B., Zhu, B., and 9 others.
|
|
<strong>Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction.</strong>
|
|
Nature Immun. 8: 1246-1254, 2007.
|
|
|
|
|
|
[PubMed: 17906628]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ni1515]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kavvoura, F. K., Akamizu, T., Awata, T., Ban, Y., Chistiakov, D. A., Frydecka, I., Ghaderi, A., Gough, S. C., Hiromatsu, Y., Ploski, R., Wang, P.-W., Ban, Y., and 16 others.
|
|
<strong>Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: a meta-analysis.</strong>
|
|
J. Clin. Endocr. Metab. 92: 3162-3170, 2007.
|
|
|
|
|
|
[PubMed: 17504905]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1210/jc.2007-0147]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kinjo, Y., Takasu, N., Komiya, I., Tomoyose, T., Takara, M., Kouki, T., Shimajiri, Y., Yabiku, K., Yoshimura, H.
|
|
<strong>Remission of Graves' hyperthyroidism and A/G polymorphism at position 49 in exon 1 of cytotoxic T lymphocyte-associated molecule-4 gene.</strong>
|
|
J. Clin. Endocr. Metab. 87: 2593-2596, 2002.
|
|
|
|
|
|
[PubMed: 12050220]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1210/jcem.87.6.8612]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kouki, T., Sawai, Y., Gardine, C. A., Fisfalen, M.-E., Alegre, M.-L., DeGroot, L. J.
|
|
<strong>CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves' disease.</strong>
|
|
J. Immun. 165: 6606-6611, 2000.
|
|
|
|
|
|
[PubMed: 11086105]
|
|
|
|
|
|
[Full Text: https://doi.org/10.4049/jimmunol.165.11.6606]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kuehn, H. S., Ouyang W., Lo, B., Deenick, E. K., Niemela, J. E., Avery, D. T., Schickel, J.-N., Tran, D. Q., Stoddard, J., Zhang, Y., Frucht, D. M., Dumitriu, B., and 24 others.
|
|
<strong>Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.</strong>
|
|
Science 345: 1623-1627, 2014.
|
|
|
|
|
|
[PubMed: 25213377]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1255904]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lee, Y. H., Harley, J. B., Nath, S. K.
|
|
<strong>CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis.</strong>
|
|
Hum. Genet. 116: 361-367, 2005.
|
|
|
|
|
|
[PubMed: 15688186]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s00439-004-1244-1]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ling, V., Wu, P. W., Finnerty, H. F., Sharpe, A. H., Gray, G. S., Collins, M.
|
|
<strong>Complete sequence determination of the mouse and human CTLA4 gene loci: cross-species DNA sequence similarity beyond exon borders.</strong>
|
|
Genomics 60: 341-355, 1999.
|
|
|
|
|
|
[PubMed: 10493833]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1006/geno.1999.5930]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Linsley, P. S., Nadler, S. G., Bajorath, J., Peach, R., Leung, H. T., Rogers, J., Bradshaw, J., Stebbins, M., Leytze, G., Brady, W., Malacko, A. R., Marquardt, H., Shaw, S.-Y.
|
|
<strong>Binding stoichiometry of the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) : a disulfide-linked homodimer binds two CD86 molecules.</strong>
|
|
J. Biol. Chem. 270: 15417-15424, 1995.
|
|
|
|
|
|
[PubMed: 7541042]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.270.25.15417]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lo, B., Zhang, K., Lu, W., Zheng, L., Zhang, Q., Kanellopoulou, C., Zhang, Y., Liu, Z., Fritz, J. M., Marsh, R., Husami, A., Kissell, D., and 21 others.
|
|
<strong>Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy.</strong>
|
|
Science 349: 436-440, 2015.
|
|
|
|
|
|
[PubMed: 26206937]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.aaa1663]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lohmueller, K. E., Pearce, C. L., Pike, M., Lander, E. S., Hirschhorn, J. N.
|
|
<strong>Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease.</strong>
|
|
Nature Genet. 33: 177-182, 2003.
|
|
|
|
|
|
[PubMed: 12524541]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng1071]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Magistrelli, G., Jeannin, P., Herbault, N., Benoit de Coignac, A., Gauchat, J.-F., Bonnefoy, J.-Y., Delneste, Y.
|
|
<strong>A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells.</strong>
|
|
Europ. J. Immun. 29: 3596-3602, 1999.
|
|
|
|
|
|
[PubMed: 10556814]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/(SICI)1521-4141(199911)29:11<3596::AID-IMMU3596>3.0.CO;2-Y]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Marron, M. P., Raffel, L. J., Garchon, H.-J., Jacob, C. O., Serrano-Rios, M., Martinez Larrad, M. T., Teng, W.-P., Park, Y., Zhang, Z.-X., Goldstein, D. R., Tao, Y.-W., Beaurain, G., Bach, J.-F., Huang, H.-S., Luo, D.-F., Zeidler, A., Rotter, J. I., Yang, M. C. K., Modilevsky, T., Maclaren, N. K., She, J.-X.
|
|
<strong>Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups.</strong>
|
|
Hum. Molec. Genet. 6: 1275-1282, 1997.
|
|
|
|
|
|
[PubMed: 9259273]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/6.8.1275]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Naluai, A. T., Nilsson, S., Samuelsson, L., Gudjonsdottir, A. H., Ascher, H., Ek, J., Hallberg, B., Kristiansson, B., Martinsson, T., Nerman, O., Sollid, L. M., Wahlstrom, J.
|
|
<strong>The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory diseases.</strong>
|
|
Tissue Antigens 56: 350-355, 2000.
|
|
|
|
|
|
[PubMed: 11098935]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1034/j.1399-0039.2000.560407.x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Nistico, L., Buzzetti, R., Pritchard, L. E., Van der Auwera, B., Giovannini, C., Bosi, E., Martinez Larrad, M. T., Serrano Rios, M., Chow, C. C., Cockram, C. S., Jacobs, K., Mijovic, C., Bain, S. C., Barnett, A. H., Vandewalle, C. L., Schuit, F., Gorus, F. K., Belgian Diabetes Registry, Tosi, R., Pozzilli, P., Todd, J. A.
|
|
<strong>The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes.</strong>
|
|
Hum. Molec. Genet. 5: 1075-1080, 1996.
|
|
|
|
|
|
[PubMed: 8817351]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/5.7.1075]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Oaks, M. K., Hallett, K. M., Penwell, R. T., Stauber, E. C., Warren, S. J., Tector, A. J.
|
|
<strong>A native soluble form of CTLA-4.</strong>
|
|
Cell. Immun. 201: 144-153, 2000.
|
|
|
|
|
|
[PubMed: 10831323]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1006/cimm.2000.1649]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Oaks, M. K., Hallett, K. M.
|
|
<strong>Cutting edge: a soluble form of CTLA-4 in patients with autoimmune thyroid disease.</strong>
|
|
J. Immun. 164: 5015-5018, 2000.
|
|
|
|
|
|
[PubMed: 10799854]
|
|
|
|
|
|
[Full Text: https://doi.org/10.4049/jimmunol.164.10.5015]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ostrov, D. A., Shi, W., Schwartz, J.-C. D., Almo, S. C., Nathenson, S. G.
|
|
<strong>Structure of murine CTLA-4 and its role in modulating T cell responsiveness.</strong>
|
|
Science 290: 816-819, 2000.
|
|
|
|
|
|
[PubMed: 11052947]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.290.5492.816]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Qureshi, O. S., Zheng, Y., Nakamura, K., Attridge, K., Manzotti, C., Schmidt, E. M., Baker, J., Jeffery, L. E., Kaur, S., Briggs, Z., Hou, T. Z., Futter, C. E., Anderson, G., Walker, L. S. K., Sansom, D. M.
|
|
<strong>Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.</strong>
|
|
Science 332: 600-603, 2011.
|
|
|
|
|
|
[PubMed: 21474713]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1202947]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Rau, H., Braun, J., Donner, H., Seissler, J., Siegmund, T., Usadel, K. H., Badenhoop, K.
|
|
<strong>The codon 17 polymorphism of the CTLA4 gene in type 2 diabetes mellitus.</strong>
|
|
J. Clin. Endocr. Metab. 86: 653-655, 2001.
|
|
|
|
|
|
[PubMed: 11158025]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1210/jcem.86.2.7204]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Reiser, H., Stadecker, M. J.
|
|
<strong>Costimulatory B7 molecules in the pathogenesis of infectious and autoimmune diseases.</strong>
|
|
New Eng. J. Med. 335: 1369-1377, 1996.
|
|
|
|
|
|
[PubMed: 8857022]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1056/NEJM199610313351807]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sayegh, M. H., Turka, L. A.
|
|
<strong>The role of T-cell costimulatory activation pathways in transplant rejection.</strong>
|
|
New Eng. J. Med. 338: 1813-1821, 1998.
|
|
|
|
|
|
[PubMed: 9632449]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1056/NEJM199806183382506]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Schneider, H., Downey, J., Smith, A., Zinselmeyer, B. H., Rush, C., Brewer, J. M., Wei, B., Hogg, N., Garside, P., Rudd, C. E.
|
|
<strong>Reversal of the TCR stop signal by CTLA-4.</strong>
|
|
Science 313: 1972-1975, 2006.
|
|
|
|
|
|
[PubMed: 16931720]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1131078]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Schubert, D., Bode, C., Kenefeck, R., Hou, T. Z., Wing, J. B., Kennedy, A., Bulashevska, A., Petersen, B.-S., Schaffer, A. A., Gruning, B. A., Unger, S., Frede, N., and 28 others.
|
|
<strong>Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.</strong>
|
|
Nature Med. 20: 1410-1416, 2014.
|
|
|
|
|
|
[PubMed: 25329329]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nm.3746]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Schwartz, J.-C. D., Zhang, X., Fedorov, A. A., Nathenson, S. G., Almo, S. C.
|
|
<strong>Structural basis for co-stimulation by the human CTLA-4/B7-2 complex.</strong>
|
|
Nature 410: 604-608, 2001.
|
|
|
|
|
|
[PubMed: 11279501]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/35069112]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Shahinian, A., Pfeffer, K., Lee, K. P., Kundig, T. M., Kishihara, K., Wakeham, A., Kawai, K., Ohashi, P. S., Thompson, C. B., Mak, T. W.
|
|
<strong>Differential T cell costimulatory requirements in CD28-deficient mice.</strong>
|
|
Science 261: 609-612, 1993.
|
|
|
|
|
|
[PubMed: 7688139]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.7688139]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Stamper, C. C., Zhang, Y., Tobin, J. F., Erbe, D. V., Ikemizu, S., Davis, S. J., Stahl, M. L., Seehra, J., Somers, W. S., Mosyak, L.
|
|
<strong>Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses.</strong>
|
|
Nature 410: 608-611, 2001. Note: Erratum: Nature 411: 617 only, 2001.
|
|
|
|
|
|
[PubMed: 11279502]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/35069118]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Thio, C. L., Mosbruger, T. L., Kaslow, R. A., Karp, C. L., Strathdee, S. A., Vlahov, D., O'Brien, S. J., Astemborski, J., Thomas, D. L.
|
|
<strong>Cytotoxic T-lymphocyte antigen 4 gene and recovery from hepatitis B virus infection.</strong>
|
|
J. Virol. 78: 11258-11262, 2004.
|
|
|
|
|
|
[PubMed: 15452244]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1128/JVI.78.20.11258-11262.2004]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Tomer, Y., Greenberg, D. A., Barbesino, G., Concepcion, E., Davies, T. F.
|
|
<strong>CTLA-4 and not CD28 is a susceptibility gene for thyroid autoantibody production.</strong>
|
|
J. Clin. Endocr. Metab. 86: 1687-1693, 2001.
|
|
|
|
|
|
[PubMed: 11297604]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1210/jcem.86.4.7372]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ueda, H., Howson, J. M. M., Esposito, L., Heward, J., Snook, H., Chamberlain, G., Rainbow, D. B., Hunter, K. M. D., Smith, A. N., DiGenova, G., Herr, M. H., Dahlman, I., and 41 others.
|
|
<strong>Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease.</strong>
|
|
Nature 423: 506-511, 2003.
|
|
|
|
|
|
[PubMed: 12724780]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature01621]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Vaidya, B., Imrie, H., Perros, P., Dickinson, J., McCarthy, M. I., Kendall-Taylor, P., Pearce, S. H. S.
|
|
<strong>Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism confers susceptibility to thyroid associated orbitopathy.</strong>
|
|
Lancet 354: 743-744, 1999.
|
|
|
|
|
|
[PubMed: 10475192]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/S0140-6736(99)01465-8]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
van Belzen, M. J., Mulder, C. J. J., Zhernakova, A., Pearson, P. L., Houwen, R. H. J., Wijmenga, C.
|
|
<strong>CTLA4 +49A/G and CT60 polymorphisms in Dutch coeliac disease patients.</strong>
|
|
Europ. J. Hum. Genet. 12: 782-785, 2004.
|
|
|
|
|
|
[PubMed: 15199380]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/sj.ejhg.5201165]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Vetizou, M., Pitt, J. M., Daillere, R., Lepage, P., Waldschmitt, N., Flament, C., Rusakiewicz, S., Routy, B., Roberti, M. P., Duong, C. P. M., Poirier-Colame, V., Roux, A., and 26 others.
|
|
<strong>Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.</strong>
|
|
Science 350: 1079-1084, 2015.
|
|
|
|
|
|
[PubMed: 26541610]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.aad1329]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
vom Berg, J., Vrohlings, M., Haller, S., Haimovici, A., Kulig, P., Sledzinska, A., Weller, M., Becher, B.
|
|
<strong>Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection.</strong>
|
|
J. Exp. Med. 210: 2803-2811, 2013.
|
|
|
|
|
|
[PubMed: 24277150]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1084/jem.20130678]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Wang, P.-W., Chen, I.-Y., Liu, R.-T., Hsieh, C.-J., Hsi, E., Juo, S.-H. H.
|
|
<strong>Cytotoxic T lymphocyte-associated molecule-4 gene polymorphism and hyperthyroid Graves' disease relapse after antithyroid drug withdrawal: a follow-up study.</strong>
|
|
J. Clin. Endocr. Metab. 92: 2513-2518, 2007.
|
|
|
|
|
|
[PubMed: 17426089]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1210/jc.2006-2761]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Wang, P.-W., Liu, R.-T., Juo, S.-H. H., Wang, S.-T., Hu, Y.-H., Hsieh, C.-J., Chen, M.-H., Chen, I.-Y., Wu, C.-L.
|
|
<strong>Cytotoxic T lymphocyte-associated molecule-4 polymorphism and relapse of Graves' hyperthyroidism after antithyroid withdrawal.</strong>
|
|
J. Clin. Endocr. Metab. 89: 169-173, 2004.
|
|
|
|
|
|
[PubMed: 14715845]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1210/jc.2003-030854]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Waterhouse, P., Penninger, J. M., Timms, E., Wakeham, A., Shahinian, A., Lee, K. P., Thompson, C. B., Griesser, H., Mak, T. W.
|
|
<strong>Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4.</strong>
|
|
Science 270: 985-988, 1995.
|
|
|
|
|
|
[PubMed: 7481803]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.270.5238.985]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T., Sakaguchi, S.
|
|
<strong>CTLA-4 control over Foxp3+ regulatory T cell function.</strong>
|
|
Science 322: 271-275, 2008.
|
|
|
|
|
|
[PubMed: 18845758]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1160062]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Zalloua, P. A., Abchee, A., Shbaklo, H., Zreik, T. G., Terwedow, H., Halaby, G., Azar, S. T.
|
|
<strong>Patients with early onset of type 1 diabetes have significantly higher GG genotype at position 49 of the CTLA4 gene.</strong>
|
|
Hum. Immun. 65: 719-724, 2004.
|
|
|
|
|
|
[PubMed: 15301861]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.humimm.2004.04.007]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Zhernakova, A., Eerligh, P., Barrera, P., Wesoly, J. Z., Huizinga, T. W. J., Roep, B. O., Wijmenga, C., Koeleman, B. P. C.
|
|
<strong>CTLA4 is differentially associated with autoimmune diseases in the Dutch population.</strong>
|
|
Hum. Genet. 118: 58-66, 2005. Note: Erratum: Hum. Genet. 119: 225 only, 2006.
|
|
|
|
|
|
[PubMed: 16025348]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s00439-005-0006-z]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
</ol>
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
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|
|
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Ada Hamosh - updated : 09/13/2016<br>Ada Hamosh - updated : 12/01/2015<br>Cassandra L. Kniffin - updated : 12/1/2014<br>Paul J. Converse - updated : 10/17/2014<br>Paul J. Converse - updated : 7/8/2014<br>Ada Hamosh - updated : 10/17/2011<br>Ada Hamosh - updated : 6/21/2011<br>Paul J. Converse - updated : 11/7/2008<br>John A. Phillips, III - updated : 10/16/2008<br>Paul J. Converse - updated : 9/11/2008<br>John A. Phillips, III - updated : 3/24/2008<br>Paul J. Converse - updated : 11/3/2006<br>Ada Hamosh - updated : 11/2/2006<br>Marla J. F. O'Neill - updated : 4/19/2006<br>Victor A. McKusick - updated : 1/30/2006<br>Marla J. F. O'Neill - updated : 12/28/2005<br>Marla J. F. O'Neill - updated : 6/21/2005<br>Victor A. McKusick - updated : 4/26/2005<br>Cassandra L. Kniffin - reorganized : 1/25/2005<br>Cassandra L. Kniffin - updated : 1/12/2005<br>Marla J. F. O'Neill - updated : 10/18/2004<br>Paul J. Converse - updated : 11/5/2003<br>Ada Hamosh - updated : 5/1/2003<br>Victor A. McKusick - updated : 1/30/2003<br>John A. Phillips, III - updated : 1/30/2003<br>Paul J. Converse - updated : 1/16/2003<br>Paul J. Converse - updated : 10/11/2002<br>John A. Phillips, III - updated : 10/24/2001<br>John A. Phillips, III - updated : 7/26/2001<br>Paul J. Converse - updated : 7/18/2001<br>Paul J. Converse - updated : 4/4/2001<br>Paul J. Converse - updated : 2/21/2001<br>Paul J. Converse - updated : 11/2/2000<br>Paul J. Converse - updated : 7/5/2000<br>John A. Phillips, III - updated : 3/6/2000<br>Victor A. McKusick - updated : 12/22/1999<br>Victor A. McKusick - updated : 7/22/1999<br>Victor A. McKusick - updated : 5/20/1999<br>Paul Brennan -updated : 12/15/1998<br>John A. Phillips, III - updated : 5/21/1998<br>Victor A. McKusick - updated : 8/22/1997<br>Alan F. Scott - updated : 11/16/1995
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Victor A. McKusick : 6/15/1989
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