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Entry
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- *188040 - THROMBOMODULIN; THBD
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- OMIM
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<div class="container hidden-print">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*188040</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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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/188040">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000178726;t=ENST00000377103" 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=7056" 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=188040" 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=ENSG00000178726;t=ENST00000377103" 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_000361" 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_000361" 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=188040" 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=01764&isoform_id=01764_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/THBD" 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/136170,220127,339657,339659,736251,4507483,19909348,31418462,37537254,119630577,193784760" 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/P07204" 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=7056" 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=ENSG00000178726;t=ENST00000377103" 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=THBD" 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=THBD" 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+7056" 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/THBD" 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:7056" 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/7056" 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=chr20&hgg_gene=ENST00000377103.3&hgg_start=23045633&hgg_end=23049672&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:11784" 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=188040[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=188040[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/ENSG00000178726" 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=THBD" 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=THBD" 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=THBD" 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=THBD&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/PA36496" 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:11784" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0001321.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:98736" 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/THBD#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:98736" 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/7056/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=7056" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00020921;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-110411-281" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7056" 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=THBD&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> 1197595004<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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188040
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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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THROMBOMODULIN; THBD
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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THRM<br />
|
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CD141 ANTIGEN; CD141
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=THBD" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">THBD</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/20/145?start=-3&limit=10&highlight=145">20p11.21</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr20:23045633-23049672&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'})">20:23,045,633-23,049,672</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
|
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Location
|
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</th>
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<th>
|
|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=612926,614486" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
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Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/20/145?start=-3&limit=10&highlight=145">
|
|
20p11.21
|
|
</a>
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
{Hemolytic uremic syndrome, atypical, susceptibility to, 6}
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/612926"> 612926 </a>
|
|
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
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<span class="mim-font">
|
|
Thrombophilia 12 due to thrombomodulin defect
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/614486"> 614486 </a>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
|
</td>
|
|
</tr>
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/188040" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<p>The THBD gene encodes thrombomodulin, an endothelial cell surface glycoprotein that forms a 1:1 complex with the coagulation factor thrombin (F2; <a href="/entry/176930">176930</a>). Binding of thrombin to this high-affinity receptor alters its specificity toward several substrates, ultimately acting as an antithrombotic factor. The F2:THBD complex activates protein C (PROC; <a href="/entry/612283">612283</a>) approximately 1,000 times faster than thrombin alone, and activated protein C degrades clotting factors V (F5; <a href="/entry/612309">612309</a>) and VIII (F8; <a href="/entry/300841">300841</a>). In addition, THBD can inhibit procoagulant functions of thrombin, such as platelet activation or fibrinogen clotting. THBD can also promote antithrombin III (SERPINC1; <a href="/entry/107300">107300</a>) inhibition of thrombin. Thus, thrombomodulin converts thrombin into a physiologic anticoagulant (summary by <a href="#5" class="mim-tip-reference" title="Esmon, N. L. <strong>Thrombomodulin.</strong> Semin. Thromb. Hemost. 13: 454-463, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2827310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2827310</a>] [<a href="https://doi.org/10.1055/s-2007-1003522" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2827310">Esmon (1987)</a> and <a href="#1" class="mim-tip-reference" title="Anastasiou, G., Gialeraki, A., Merkouri, E., Politou, M., Travlou, A. <strong>Thrombomodulin as a regulator of the anticoagulant pathway: implication in the development of thrombosis.</strong> Blood Coagul. Fibrinolysis 23: 1-10, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036808</a>] [<a href="https://doi.org/10.1097/MBC.0b013e32834cb271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22036808">Anastasiou et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2827310+22036808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#25" class="mim-tip-reference" title="Wen, D., Dittman, W. A., Ye, R. D., Deaven, L. L., Majerus, P. W., Sadler, J. E. <strong>Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene.</strong> Biochemistry 26: 4350-4357, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2822087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2822087</a>] [<a href="https://doi.org/10.1021/bi00388a025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2822087">Wen et al. (1987)</a> presented the complete cDNA sequence of human thrombomodulin. The sequence encodes a 60.3-kD protein of 575 amino acids. The predicted protein sequence includes a signal peptide of about 21 amino acids, an amino terminal ligand-binding domain of about 223 amino acids, an epidermal growth factor (EGF) homology region (see <a href="/entry/131530">131530</a>) of 236 amino acids, a serine/threonine-rich segment of 34 amino acids, a membrane-spanning domain of 23 amino acids, and a cytoplasmic tail of 38 amino acids. The EGF homology region consists of 6 tandemly repeated EGF-like domains. The organization of thrombomodulin is similar to that of LDL receptor (<a href="/entry/606945">606945</a>), and the protein is homologous to a large number of other proteins that also contain EGF-like domains, including factor VII (<a href="/entry/613878">613878</a>), factor IX (<a href="/entry/300746">300746</a>), factor X (<a href="/entry/613872">613872</a>), factor XII (<a href="/entry/610619">610619</a>), protein C, tissue plasminogen activator (<a href="/entry/173370">173370</a>), and urokinase (<a href="/entry/191840">191840</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2822087" 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="#12" class="mim-tip-reference" title="Jackman, R. W., Beeler, D. L., Fritze, L., Soff, G., Rosenberg, R. D. <strong>Human thrombomodulin gene is intron depleted: nucleic acid sequences of the cDNA and gene predict protein structure and suggest sites of regulatory control.</strong> Proc. Nat. Acad. Sci. 84: 6425-6429, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2819876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2819876</a>] [<a href="https://doi.org/10.1073/pnas.84.18.6425" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2819876">Jackman et al. (1987)</a> reviewed the structure of the thrombomodulin gene and commented on the lack of introns. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2819876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By molecular hybridization to sorted chromosomes, <a href="#25" class="mim-tip-reference" title="Wen, D., Dittman, W. A., Ye, R. D., Deaven, L. L., Majerus, P. W., Sadler, J. E. <strong>Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene.</strong> Biochemistry 26: 4350-4357, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2822087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2822087</a>] [<a href="https://doi.org/10.1021/bi00388a025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2822087">Wen et al. (1987)</a> localized the structural gene for thrombomodulin to chromosome 20. By in situ hybridization, <a href="#6" class="mim-tip-reference" title="Espinosa, R., III, Sadler, J. E., Le Beau, M. M. <strong>Regional localization of the human thrombomodulin gene to 20p12-cen.</strong> Genomics 5: 649-650, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2559025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2559025</a>] [<a href="https://doi.org/10.1016/0888-7543(89)90038-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2559025">Espinosa et al. (1989)</a> localized the THBD gene to 20p12-cen. By FISH, <a href="#27" class="mim-tip-reference" title="Yasuda, K., Espinosa, R., III, Davis, E. M., Le Beau, M. M., Bell, G. I. <strong>Human somatostatin receptor genes: localization of SSTR5 to human chromosome 20p11.2.</strong> Genomics 17: 785-786, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8244401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8244401</a>] [<a href="https://doi.org/10.1006/geno.1993.1410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8244401">Yasuda et al. (1993)</a> assigned the THBD gene to 20p11, proximal to NEC2 (<a href="/entry/162151">162151</a>) and SSTR5 (<a href="/entry/182455">182455</a>) which are located at 20p11.2. By radiation hybrid mapping, <a href="#17" class="mim-tip-reference" title="Maglott, D. R., Feldblyum, T. V., Durkin, A. S., Nierman, W. C. <strong>Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p).</strong> Mammalian Genome 7: 400-401, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661740/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661740</a>] [<a href="https://doi.org/10.1007/s003359900120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8661740">Maglott et al. (1996)</a> localized the THBD gene to a region corresponding to 20p11.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8244401+8661740+2559025+2822087" 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="#11" class="mim-tip-reference" title="Ishii, H., Majerus, P. W. <strong>Thrombomodulin is present in human plasma and urine.</strong> J. Clin. Invest. 76: 2178-2181, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3001144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3001144</a>] [<a href="https://doi.org/10.1172/JCI112225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3001144">Ishii and Majerus (1985)</a> demonstrated thrombomodulin in human plasma and urine. The physiologic significance of circulating and urinary thrombomodulin was obscure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3001144" 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>Malignant primary tumors of the pericardium such as primary pericardial mesothelioma are very rare. Thrombomodulin has been identified on the pleural mesothelioma cells. <a href="#22" class="mim-tip-reference" title="Okura, Y., Kato, K., Hanawa, H., Izumi, T., Kamishima, T., Yamato, Y., Emura, I., Shibata, A. <strong>Pericardial mesothelioma secreting thrombomodulin.</strong> Am. Heart J. 132: 1309-1311, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8969598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8969598</a>] [<a href="https://doi.org/10.1016/s0002-8703(96)90490-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8969598">Okura et al. (1996)</a> described the case of a 25-year-old man who was found to have a pericardial mesothelioma secreting thrombomodulin. Very little clot formation in the pericardial space may have been the result of the anticoagulant effect of thrombomodulin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8969598" 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 microarray technology to identify CLOCK (<a href="/entry/601851">601851</a>)-controlled genes in human and murine vascular endothelial cells, <a href="#23" class="mim-tip-reference" title="Takeda, N., Maemura, K., Horie, S., Oishi, K., Imai, Y., Harada, T., Saito, T., Shiga, T., Amiya, E., Manabe, I., Ishida, N., Nagai, R. <strong>Thrombomodulin is a clock-controlled gene in vascular endothelial cells.</strong> J. Biol. Chem. 282: 32561-32567, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17848551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17848551</a>] [<a href="https://doi.org/10.1074/jbc.M705692200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17848551">Takeda et al. (2007)</a> found that thrombomodulin was upregulated by CLOCK in these cells. Thbd mRNA and protein showed a clear circadian oscillation in murine heart and lung. A heterodimer of CLOCK and BMAL2 (ARNTL2; <a href="/entry/614517">614517</a>) bound directly to the E-box of the THBD promoter, resulting in activation. The phase of circadian oscillation of Thbd mRNA expression was altered by temporal feeding restriction in mice, suggesting that gene expression is regulated by the peripheral clock system. In addition, this circadian oscillation of Thbd was not seen in Clock mutant mice. The data suggested that there is a peripheral clock in vascular endothelial cells that regulates THBD gene expression, and that the oscillation of this expression may contribute to the circadian variation of cardiovascular events. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17848551" 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 in vitro cellular studies, <a href="#3" class="mim-tip-reference" title="Delvaeye, M., Noris, M., De Vriese, A., Esmon, C. T., Esmon, N. L., Ferrell, G., Del-Favero, J., Plaisance, S., Claes, B., Lambrechts, D., Zoja, C., Remuzzi, G., Conway, E. M. <strong>Thrombomodulin mutations in atypical hemolytic-uremic syndrome.</strong> New Eng. J. Med. 361: 345-357, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19625716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19625716</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19625716[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/10.1056/NEJMoa0810739" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19625716">Delvaeye et al. (2009)</a> demonstrated that thrombomodulin binds to C3b (see <a href="/entry/120700">120700</a>) and factor H (CFH; <a href="/entry/134370">134370</a>) and negatively regulates complement by accelerating factor I (CFI; <a href="/entry/217030">217030</a>)-mediated inactivation of C3b in the presence of cofactors. By promoting activation of the plasma procarboxypeptidase B (CPB2; <a href="/entry/603101">603101</a>), thrombomodulin also accelerates the inactivation of anaphylatoxins C3a and C5a. Thus, thrombomodulin provides protection against complement activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19625716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>As part of an effort to clarify the nomenclature for monocytes and dendritic cells (DCs) in blood, <a href="#28" class="mim-tip-reference" title="Ziegler-Heitbrock, L., Ancuta, P., Crowe, S., Dalod, M., Grau, V., Hart, D. N., Leenen, P. J. M., Liu, Y.-J., MacPherson, G., Randolph, G. J., Scherberich, J., Schmitz, J., Shortman, K., Sozzani, S., Strobl, H., Zembala, M., Austyn, J. M., Lutz, M. B. <strong>Nomenclature of monocytes and dendritic cells in blood.</strong> Blood 116: e74-e80, 2010. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20628149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20628149</a>] [<a href="https://doi.org/10.1182/blood-2010-02-258558" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20628149">Ziegler-Heitbrock et al. (2010)</a> reported that CD141 is a marker for 1 of 2 types of myeloid DCs. CD141-positive myeloid DCs represent an immature or precursor stage of circulating DCs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20628149" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Thrombophilia Due to Thrombomodulin Defect</em></strong></p><p>
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The role of thrombomodulin in thrombosis (THPH12; <a href="/entry/614486">614486</a>) is controversial. Although there have been several reports of THBD mutations in patients with venous thrombosis, clear functional evidence for the pathogenicity of these mutations is lacking. In a review, <a href="#1" class="mim-tip-reference" title="Anastasiou, G., Gialeraki, A., Merkouri, E., Politou, M., Travlou, A. <strong>Thrombomodulin as a regulator of the anticoagulant pathway: implication in the development of thrombosis.</strong> Blood Coagul. Fibrinolysis 23: 1-10, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036808</a>] [<a href="https://doi.org/10.1097/MBC.0b013e32834cb271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22036808">Anastasiou et al. (2012)</a> noted that thrombomodulin has a major role in capillary beds and that THBD variation may not be associated with large vessel thrombosis. It is likely that genetic or environmental risk factors in addition to THBD variation are involved in the pathogenesis of venous thrombosis. However, variation in the THBD gene may be associated with increased risk for arterial thrombosis and myocardial infarction. This association may be attributed to the fact that thrombomodulin modulates inflammatory processes, complement activity, and fibrinolysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22036808" 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>Late fetal loss can be associated with placental insufficiency and coagulation defects. Thrombomodulin and the endothelial protein C receptor (EPCR; <a href="/entry/600646">600646</a>) are glycoprotein receptors expressed mainly on the endothelial surface of blood vessels and also in the placenta; they both play a key physiologic role in the protein C anticoagulant pathway. <a href="#8" class="mim-tip-reference" title="Franchi, F., Biguzzi, E., Cetin, I., Facchetti, F., Radaelli, T., Bozzo, M., Pardi, G., Faioni, E. M. <strong>Mutations in the thrombomodulin and endothelial protein C receptor genes in women with late fetal loss.</strong> Brit. J. Haemat. 114: 641-646, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11552992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11552992</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2001.02964.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11552992">Franchi et al. (2001)</a> investigated the possibility that defects in these proteins play an important role in the pathogenesis of late fetal loss. They performed a case-control study in 95 women with unexplained late fetal loss (after 20 weeks); the control group comprised 236 women who had given birth to at least 1 healthy baby and had no history of late fetal loss or obstetrical complications. In the 95 patients, they found 5 mutations in the THBD gene and 2 in the EPCR gene; in the 236 control subjects, they found 3 mutations in the THBD gene and 1 in the EPCR gene. The relative risk for late fetal loss for carriers of mutation in either the THBD or EPCR gene was estimated by an odds ratio of 4.0. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11552992" 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 evaluate the contribution of THBD gene mutations to venous thrombosis, <a href="#7" class="mim-tip-reference" title="Faioni, E. M., Franchi, F., Castaman, G., Biguzzi, E., Rodeghiero, F. <strong>Mutations in the thrombomodulin gene are rare in patients with severe thrombophilia.</strong> Brit. J. Haemat. 118: 595-599, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12139752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12139752</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2002.03644.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12139752">Faioni et al. (2002)</a> examined 38 patients with recurrent, documented thrombotic events at a young age and a positive family history. Twelve individuals with low levels of soluble thrombomodulin in plasma were also studied. Two mutations were identified: -33G-A (<a href="#0004">188040.0004</a>), in a severely thrombophilic patient, and D468Y (<a href="#0001">188040.0001</a>). The allelic frequency of an ala455-to-val polymorphism (A455V; <a href="#0008">188040.0008</a>) was identical in patients and controls. <a href="#7" class="mim-tip-reference" title="Faioni, E. M., Franchi, F., Castaman, G., Biguzzi, E., Rodeghiero, F. <strong>Mutations in the thrombomodulin gene are rare in patients with severe thrombophilia.</strong> Brit. J. Haemat. 118: 595-599, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12139752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12139752</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2002.03644.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12139752">Faioni et al. (2002)</a> concluded that mutations in the THBD gene are a very rare cause of severe thrombophilia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12139752" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Tang, L., Wang, H.-F., Lu, X., Jian, X.-R., Jin, B., Zheng, H., Li, Y.-Q., Wang, Q.-Y., Wu, T.-C., Guo, H., Liu, H., Guo, T., Yu, J.-M., Yang, R., Yang, Y., Hu, Y. <strong>Common genetic risk factors for venous thrombosis in the Chinese population.</strong> Am. J. Hum. Genet. 92: 177-187, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23332921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23332921</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23332921[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23332921">Tang et al. (2013)</a> studied venous thrombosis in the Chinese population, examining 1,304 individuals diagnosed with a first venous thrombosis and 1,334 age- and sex-matched healthy participants. Resequencing of THBD in 60 individuals with venous thrombosis and in 60 controls, and a functional assay, showed that a common variant, c.-151G-T (<a href="#0010">188040.0010</a>), in the 5-prime UTR significantly reduced the gene expression and could cause a predisposition to venous thrombosis. This variant was then genotyped in a case-control study, and results indicated that heterozygotes had a 2.80-fold (95% confidence interval = 1.88-4.29) increased risk of venous thrombosis. The THBD c.-151G-T variant was further investigated in a family analysis involving 176 first-degree relatives from 38 index families. First-degree relatives with this variant had a 3.42-fold increased risk of venous thrombosis, and their probability of remaining thrombosis-free was significantly lower than that of relatives without the variant. In addition, 5 rare mutations that might be deleterious were also identified in thrombophilic individuals by sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23332921" 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>Susceptibility to Atypical Hemolytic Uremic Syndrome 6</em></strong></p><p>
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In 7 (4.6%) of 153 patients with atypical hemolytic uremic syndrome (AHUS6; <a href="/entry/612926">612926</a>), <a href="#3" class="mim-tip-reference" title="Delvaeye, M., Noris, M., De Vriese, A., Esmon, C. T., Esmon, N. L., Ferrell, G., Del-Favero, J., Plaisance, S., Claes, B., Lambrechts, D., Zoja, C., Remuzzi, G., Conway, E. M. <strong>Thrombomodulin mutations in atypical hemolytic-uremic syndrome.</strong> New Eng. J. Med. 361: 345-357, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19625716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19625716</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19625716[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/10.1056/NEJMoa0810739" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19625716">Delvaeye et al. (2009)</a> identified 6 different heterozygous mutations in the THBD gene (see, e.g., <a href="#0005">188040.0005</a>-<a href="#0007">188040.0007</a>). In vitro functional expression studies showed that cells transfected with mutant THBD were less effective in converting C3b to iC3b on the cell surface after complement activation, and were thus not as well protected against complement activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19625716" 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="#10" class="mim-tip-reference" title="Isermann, B., Sood, R., Pawlinski, R., Zogg, M., Kalloway, S., Degen, J. L., Mackman, N., Weiler, H. <strong>The thrombomodulin-protein C system is essential for the maintenance of pregnancy.</strong> Nature Med. 9: 331-337, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12579195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12579195</a>] [<a href="https://doi.org/10.1038/nm825" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12579195">Isermann et al. (2003)</a> found that disruption of the mouse thrombomodulin gene leads to embryonic lethality caused by a defect in the placenta. They showed that the abortion of thrombomodulin-deficient embryos is caused by tissue factor (<a href="/entry/134390">134390</a>)-initiated activation of the blood coagulation cascade at the fetomaternal interface. Activated coagulation factors induced cell death and growth inhibition of placental trophoblast cells by 2 distinct mechanisms. The death of giant trophoblast cells was caused by the conversion of fibrinogen to fibrin (see <a href="/entry/134820">134820</a>) and subsequent formation of fibrin degradation products. In contrast, the growth arrest of trophoblast cells is not mediated by fibrin, but is a likely result of engagement of the protease-activated receptors PAR2 (<a href="/entry/600933">600933</a>) and PAR4 (<a href="/entry/602779">602779</a>) by coagulation factors. <a href="#10" class="mim-tip-reference" title="Isermann, B., Sood, R., Pawlinski, R., Zogg, M., Kalloway, S., Degen, J. L., Mackman, N., Weiler, H. <strong>The thrombomodulin-protein C system is essential for the maintenance of pregnancy.</strong> Nature Med. 9: 331-337, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12579195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12579195</a>] [<a href="https://doi.org/10.1038/nm825" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12579195">Isermann et al. (2003)</a> concluded that their findings show a novel function for the thrombomodulin-protein C system in controlling the growth and survival of trophoblast cells in the placenta. This function is essential for the maintenance of pregnancy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12579195" 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> rs41348347 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs41348347;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/rs41348347?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=rs41348347" 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=rs41348347" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>This variant, formerly titled THROMBOPHILIA DUE TO THROMBOMODULIN DEFECT (<a href="/entry/614486">614486</a>), has been reclassified based on the findings of <a href="#18" class="mim-tip-reference" title="Nakazawa, F., Koyama, T., Saito, T., Shibakura, M., Yoshinaga, H., Chung, D. H., Kamiyama, R., Hirosawa, S. <strong>Thrombomodulin with the Asp468Tyr mutation is expressed on the cell surface with normal cofactor activity for protein C activation.</strong> Brit. J. Haemat. 106: 416-420, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10460600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10460600</a>] [<a href="https://doi.org/10.1046/j.1365-2141.1999.01567.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10460600">Nakazawa et al. (1999)</a> and <a href="#14" class="mim-tip-reference" title="Kunz, G., Ohlin, A.-K., Adami, A., Zoller, B., Svensson, P., Lane, D. A. <strong>Naturally occurring mutations in the thrombomodulin gene leading to impaired expression and function.</strong> Blood 99: 3646-3653, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11986219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11986219</a>] [<a href="https://doi.org/10.1182/blood.v99.10.3646" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11986219">Kunz et al. (2002)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10460600+11986219" 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 45-year-old Hispanic man who developed a pulmonary embolism, <a href="#21" class="mim-tip-reference" title="Ohlin, A.-K., Marlar, R. A. <strong>The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease.</strong> Blood 85: 330-336, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7811989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7811989</a>]" pmid="7811989">Ohlin and Marlar (1995)</a> identified a heterozygous 1456G-T transversion in the THBD gene, resulting in an asp468-to-tyr (D468Y) substitution between the transmembrane domain and the sixth EGF-like domain. He had decreased soluble THBD fragments in serum compared to controls. The patient's mother died suddenly, apparently of pulmonary embolus; his 23-year-old son, who had no history of thrombosis, was heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7811989" 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="Nakazawa, F., Koyama, T., Saito, T., Shibakura, M., Yoshinaga, H., Chung, D. H., Kamiyama, R., Hirosawa, S. <strong>Thrombomodulin with the Asp468Tyr mutation is expressed on the cell surface with normal cofactor activity for protein C activation.</strong> Brit. J. Haemat. 106: 416-420, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10460600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10460600</a>] [<a href="https://doi.org/10.1046/j.1365-2141.1999.01567.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10460600">Nakazawa et al. (1999)</a> demonstrated that the D468Y variant protein was expressed normally at the cell surface in COS-7 cells and had normal cofactor activity for activation of protein C. In addition, the Km and Vmax of the variant protein were similar to wildtype, casting doubt on its pathogenicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10460600" 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="Faioni, E. M., Franchi, F., Castaman, G., Biguzzi, E., Rodeghiero, F. <strong>Mutations in the thrombomodulin gene are rare in patients with severe thrombophilia.</strong> Brit. J. Haemat. 118: 595-599, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12139752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12139752</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2002.03644.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12139752">Faioni et al. (2002)</a> identified a heterozygous D468Y substitution in 1 of 12 patients with thrombophilia and low serum THBD levels. The patient was a 52-year-old woman with deep vein thrombosis of the lower limb and a stroke. However, <a href="#7" class="mim-tip-reference" title="Faioni, E. M., Franchi, F., Castaman, G., Biguzzi, E., Rodeghiero, F. <strong>Mutations in the thrombomodulin gene are rare in patients with severe thrombophilia.</strong> Brit. J. Haemat. 118: 595-599, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12139752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12139752</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2002.03644.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12139752">Faioni et al. (2002)</a> noted that there is no evidence to support the frequent involvement of THBD mutations in large vessel thrombosis, if at all, and suggested that THBD defects be sought only for research purposes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12139752" 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="Kunz, G., Ohlin, A.-K., Adami, A., Zoller, B., Svensson, P., Lane, D. A. <strong>Naturally occurring mutations in the thrombomodulin gene leading to impaired expression and function.</strong> Blood 99: 3646-3653, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11986219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11986219</a>] [<a href="https://doi.org/10.1182/blood.v99.10.3646" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11986219">Kunz et al. (2002)</a> found no abnormality in cell surface expression or thrombomodulin cofactor function in studies of the D468Y protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11986219" 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">rs2122673257 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2122673257;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=rs2122673257" 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=rs2122673257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 unrelated patients with thrombophilia due to thrombomodulin defect (<a href="/entry/614486">614486</a>), <a href="#4" class="mim-tip-reference" title="Doggen, C. J. M., Kunz, G., Rosendaal, F. R., Lane, D. A., Vos, H. L., Stubbs, P. J., Cats, V. M., Ireland, H. <strong>A mutation in the thrombomodulin gene, 127G to A coding for ala25-to-thr, and the risk of myocardial infarction in men.</strong> Thromb. Haemost. 80: 743-748, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843165</a>]" pmid="9843165">Doggen et al. (1998)</a> identified a heterozygous 127G-A mutation in the THBD gene, resulting in an ala25-to-thr (A25T) substitution. The patients were ascertained from a larger cohort of 104 patients with myocardial infarction. In a larger study of 560 men with a first myocardial infarction before the age of 70, <a href="#4" class="mim-tip-reference" title="Doggen, C. J. M., Kunz, G., Rosendaal, F. R., Lane, D. A., Vos, H. L., Stubbs, P. J., Cats, V. M., Ireland, H. <strong>A mutation in the thrombomodulin gene, 127G to A coding for ala25-to-thr, and the risk of myocardial infarction in men.</strong> Thromb. Haemost. 80: 743-748, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843165</a>]" pmid="9843165">Doggen et al. (1998)</a> found that 12 were carriers of the A25T substitution. In a control group of 646 men, frequency-matched for age, 7 were carriers of the A25T substitution. The allelic frequencies were 1.07% among patients and 0.54% among controls, suggesting an odds ratio of 2.0. In patients below age 50, the predicted risk was almost 7 times increased (odds ratio, 6.5). In the presence of smoking or a metabolic risk factor, the predicted risk increased to 9-fold and 4-fold, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843165" 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 42-year-old Swedish woman with thrombophilia due to thrombomodulin defect who developed a sagittal sinus thrombosis causing neurologic symptoms, <a href="#20" class="mim-tip-reference" title="Norlund, L., Zoller, B., Ohlin, A.-K. <strong>A novel thrombomodulin gene mutation in a patient suffering from sagittal sinus thrombosis.</strong> Thromb. Haemost. 78: 1164-1166, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9364978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9364978</a>]" pmid="9364978">Norlund et al. (1997)</a> identified a heterozygous A25T mutation. She had been taking oral contraceptives for 18 years. Her unaffected 16-year-old daughter also carried the mutation. The substitution is located in a conserved residue in the N terminal, lectin-like extracellular domain of the protein, which may be involved in regulation of cell surface expression of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9364978" 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="Kunz, G., Ohlin, A.-K., Adami, A., Zoller, B., Svensson, P., Lane, D. A. <strong>Naturally occurring mutations in the thrombomodulin gene leading to impaired expression and function.</strong> Blood 99: 3646-3653, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11986219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11986219</a>] [<a href="https://doi.org/10.1182/blood.v99.10.3646" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11986219">Kunz et al. (2002)</a> found no abnormality in cell surface expression or thrombomodulin cofactor function in studies of the A25T protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11986219" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a man with thrombophilia due to thrombomodulin defect (<a href="/entry/614486">614486</a>) resulting in an occlusive myocardial infarction at age 52 years, <a href="#13" class="mim-tip-reference" title="Kunz, G., Ireland, H. A., Stubbs, P. J., Kahan, M., Coulton, G. C., Lane, D. A. <strong>Identification and characterization of a thrombomodulin gene mutation coding for an elongated protein with reduced expression in a kindred with myocardial infarction.</strong> Blood 95: 569-576, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10627464/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10627464</a>]" pmid="10627464">Kunz et al. (2000)</a> found a heterozygous frameshift insertion mutation, 1689insT, in the THBD gene. The mutation predicts an elongated gene product because of substitution of the last 12 C-terminal amino acids by 61 abnormal residues. Pedigree analysis suggested that a brother who had suffered a fatal myocardial infarction probably also carried the mutation. Known risk factors for myocardial infarction, including smoking, increased blood pressure, elevated triglycerides, and elevated cholesterol, were present in the proband and other family members. Carriers of the mutant allele expressed significantly lower amounts of thrombomodulin on the surface of their monocytes and lower levels of soluble thrombomodulin in plasma. Transfection of the mutation in COS-7 cells resulted in reduced cell surface expression of mutant THBD associated with impaired translocation through the endoplasmic reticulum/Golgi apparatus compared to wildtype. In addition, cells expressing abnormal thrombomodulin had a 2.5-fold reduced ability to accelerate the thrombin (F2; <a href="/entry/176930">176930</a>)-mediated activation of protein C (PROC; <a href="/entry/612283">612283</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10627464" 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> rs13306848 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs13306848;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/rs13306848?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=rs13306848" 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=rs13306848" 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="#9" class="mim-tip-reference" title="Ireland, H., Kunz, G., Kyriakoulis, K., Stubbs, P. J., Lane, D. A. <strong>Thrombomodulin gene mutations associated with myocardial infarction.</strong> Circulation 96: 15-18, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9236408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9236408</a>] [<a href="https://doi.org/10.1161/01.cir.96.1.15" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9236408">Ireland et al. (1997)</a> identified a heterozygous -33G-A transition in the promoter region of the THBD gene adjacent to the TATA in 1 of 104 patients with myocardial infarction (<a href="/entry/614486">614486</a>) and in 1 control. Both individuals were of Asian origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9236408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Le Flem, L., Picard, V., Emmerich, J., Gandrille, S., Fiessinger, J.-N., Aiach, M., Alhenc-Gelas, M. <strong>Mutations in promoter region of thrombomodulin and venous thromboembolic disease.</strong> Arterioscler. Thromb. Vasc. Biol. 19: 1098-1104, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10195941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10195941</a>] [<a href="https://doi.org/10.1161/01.atv.19.4.1098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10195941">Le Flem et al. (1999)</a> identified a heterozygous -33G-A transition in the THBD gene in 2 (0.97%) of 205 patients with venous thromboembolic disease and in 1 (0.25%) of 394 controls, suggesting that it may be a risk factor. However, in vitro functional expression assays indicated that the -33G-A change caused only a mild decrease in promoter activity, suggesting that it may not be a risk factor for venous thrombosis by lowering the expression of THBD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10195941" 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>Among 320 Chinese patients with coronary artery disease and 200 matched controls, <a href="#16" class="mim-tip-reference" title="Li, Y.-H., Chen, J.-H., Wu, H.-L., Shi, G.-Y., Huang, H.-C., Chao, T.-H., Tsai, W.-C., Tsai, L.-M., Guo, H.-R., Wu, W.-S., Chen, Z.-C. <strong>G-33A mutation in the promoter region of thrombomodulin gene and its association with coronary artery disease and plasma soluble thrombomodulin levels.</strong> Am. J. Cardiol. 85: 8-12, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11078228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11078228</a>] [<a href="https://doi.org/10.1016/s0002-9149(99)00597-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11078228">Li et al. (2000)</a> found a significant association between the -33G-A variant and disease. The GA and AA genotypes were found in 23.8% of patients compared to 15.5% of controls (OR of 1.70, p = 0.031). The soluble thrombomodulin level was significantly higher in patients compared to controls, was higher in patients with the GG genotype compared to those with the GA or AA genotype, and increased with more severe disease in those with the GG genotype, but not in those with the GA or AA genotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11078228" 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="Faioni, E. M., Franchi, F., Castaman, G., Biguzzi, E., Rodeghiero, F. <strong>Mutations in the thrombomodulin gene are rare in patients with severe thrombophilia.</strong> Brit. J. Haemat. 118: 595-599, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12139752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12139752</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2002.03644.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12139752">Faioni et al. (2002)</a> examined 38 patients with recurrent, documented thrombotic events at a young age and a positive family history. One patient with thrombophilia was found to have a heterozygous -33G-A transition (also known as -201G-A in another numbering system) in the promoter region of the THBD gene. This patient had a deep venous thrombosis of a lower limb at age 39 years, followed by 3 recurrent events at age 40, including a pulmonary embolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12139752" 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> rs1800576 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1800576;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/rs1800576?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=rs1800576" 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=rs1800576" 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=RCV000013555 OR RCV000886689 OR RCV001328105 OR RCV001818154 OR RCV003914835" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013555, RCV000886689, RCV001328105, RCV001818154, RCV003914835" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013555...</a>
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<p>In a 24-year-old man with recurrent AHUS6 (<a href="/entry/612926">612926</a>) since age 1 year, <a href="#3" class="mim-tip-reference" title="Delvaeye, M., Noris, M., De Vriese, A., Esmon, C. T., Esmon, N. L., Ferrell, G., Del-Favero, J., Plaisance, S., Claes, B., Lambrechts, D., Zoja, C., Remuzzi, G., Conway, E. M. <strong>Thrombomodulin mutations in atypical hemolytic-uremic syndrome.</strong> New Eng. J. Med. 361: 345-357, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19625716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19625716</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19625716[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/10.1056/NEJMoa0810739" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19625716">Delvaeye et al. (2009)</a> identified a heterozygous mutation in the THBD gene, resulting in an ala43-to-thr (A43T) substitution in the lectin-like domain of the protein. He had had several episodes of aHUS in infancy, leading to chronic renal failure. Serum C3 (<a href="/entry/120700">120700</a>) was decreased, consistent with activation of the alternative complement pathway. He had 8 sibs, 3 of whom had died during acute episodes of aHUS. A sister, who also carried the A43T mutation, had had 1 aHUS episode during infancy. The unaffected mother and another unaffected sib were also heterozygous carriers. In vitro functional expression studies showed that cells transfected with mutant THBD were less effective in converting C3b to iC3b on the cell surface after complement activation, and were thus not as well protected against complement activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19625716" 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 HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 6</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918667 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918667;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/rs121918667?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=rs121918667" 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=rs121918667" 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=RCV000013556" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013556" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013556</a>
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<p>In a boy with AHUS6 (<a href="/entry/612926">612926</a>), <a href="#3" class="mim-tip-reference" title="Delvaeye, M., Noris, M., De Vriese, A., Esmon, C. T., Esmon, N. L., Ferrell, G., Del-Favero, J., Plaisance, S., Claes, B., Lambrechts, D., Zoja, C., Remuzzi, G., Conway, E. M. <strong>Thrombomodulin mutations in atypical hemolytic-uremic syndrome.</strong> New Eng. J. Med. 361: 345-357, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19625716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19625716</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19625716[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/10.1056/NEJMoa0810739" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19625716">Delvaeye et al. (2009)</a> identified a heterozygous mutation in the THBD gene, resulting in an asp53-to-gly (D53G) substitution in the lectin-like domain of the protein. He had recurrent episodes since age 6 months and 1 sib who had died of aHUS. The unaffected mother and an unaffected brother also carried the mutation. In vitro functional expression studies showed that cells transfected with mutant THBD were less effective in converting C3b to iC3b on the cell surface after complement activation, and were thus not as well protected against complement activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19625716" 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>.0007 HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 6</strong>
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THBD, PRO495SER
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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> rs1800578 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1800578;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/rs1800578?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=rs1800578" 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=rs1800578" 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=RCV000013557 OR RCV000899504 OR RCV001328104 OR RCV003313772 OR RCV003944819" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013557, RCV000899504, RCV001328104, RCV003313772, RCV003944819" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013557...</a>
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<p>In a girl with recurrent AHUS6 (<a href="/entry/612926">612926</a>) since childhood and residual renal dysfunction, <a href="#3" class="mim-tip-reference" title="Delvaeye, M., Noris, M., De Vriese, A., Esmon, C. T., Esmon, N. L., Ferrell, G., Del-Favero, J., Plaisance, S., Claes, B., Lambrechts, D., Zoja, C., Remuzzi, G., Conway, E. M. <strong>Thrombomodulin mutations in atypical hemolytic-uremic syndrome.</strong> New Eng. J. Med. 361: 345-357, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19625716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19625716</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19625716[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/10.1056/NEJMoa0810739" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19625716">Delvaeye et al. (2009)</a> identified a heterozygous mutation in the THBD gene, resulting in a pro495-to-ser (P495S) substitution in the serine-threonine-rich region of the protein. Serum C3 (<a href="/entry/120700">120700</a>) was decreased. In vitro functional expression studies showed that cells transfected with mutant THBD were less effective in converting C3b to iC3b on the cell surface after complement activation, and were thus not as well protected against complement activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19625716" 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> rs1042579 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1042579;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/rs1042579?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=rs1042579" 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=rs1042579" 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=RCV000302594 OR RCV001516722 OR RCV001643035 OR RCV002294300 OR RCV003969973" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000302594, RCV001516722, RCV001643035, RCV002294300, RCV003969973" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000302594...</a>
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<p>This common polymorphism in the THBD gene, a 1418C-T transition resulting in an ala455-to-val (A455V) substitution in the sixth EGF-like domain in the thrombin-binding domain (<a href="#2" class="mim-tip-reference" title="Cole, J. W., Roberts, S. C., Gallagher, M., Giles, W. H., Mitchell, B. D., Steinberg, K. K., Wozniak, M. A., Macko, R. F., Reinhart, L. J., Kittner, S. J. <strong>Thrombomodulin ala455val polymorphism and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study.</strong> BMC Neurol. 4: 21-27, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15574195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15574195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15574195[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/10.1186/1471-2377-4-21" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15574195">Cole et al., 2004</a>), is classified as a variant of unknown significance because there are conflicting reports about its role in thrombophilia and myocardial infarction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15574195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Norlund, L., Holm, J., Zoller, B., Ohlin, A.-K. <strong>A common thrombomodulin amino acid dimorphism is associated with myocardial infarction.</strong> Thromb. Haemost. 77: 248-251, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9157575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9157575</a>]" pmid="9157575">Norlund et al. (1997)</a> found an association between the A455V substitution in the THBD gene and the development of premature myocardial infarction (MI). Among 97 MI survivors and 159 controls, the C allele (ala455) was significantly more frequent among patients than controls (0.82 compared to 0.72; p = 0.035). <a href="#19" class="mim-tip-reference" title="Norlund, L., Holm, J., Zoller, B., Ohlin, A.-K. <strong>A common thrombomodulin amino acid dimorphism is associated with myocardial infarction.</strong> Thromb. Haemost. 77: 248-251, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9157575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9157575</a>]" pmid="9157575">Norlund et al. (1997)</a> suggested that the A455V substitution may affect the function of thrombomodulin and activation of the protein C anticoagulant pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9157575" 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>Among 104 patients with MI who had no history of thrombotic episodes and 104 controls, <a href="#9" class="mim-tip-reference" title="Ireland, H., Kunz, G., Kyriakoulis, K., Stubbs, P. J., Lane, D. A. <strong>Thrombomodulin gene mutations associated with myocardial infarction.</strong> Circulation 96: 15-18, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9236408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9236408</a>] [<a href="https://doi.org/10.1161/01.cir.96.1.15" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9236408">Ireland et al. (1997)</a> found no association between disease and the A455V variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9236408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a cohort of 376 patients (23% black, 77% white) with coronary heart disease, including MI, and 461 controls, <a href="#26" class="mim-tip-reference" title="Wu, K. K., Aleksic, N., Ahn, C., Boerwinkle, E., Folsom, A. R., Juneja, H. <strong>Thrombomodulin ala455val polymorphism and risk of coronary heart disease.</strong> Circulation 103: 1386-1389, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11245641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11245641</a>] [<a href="https://doi.org/10.1161/01.cir.103.10.1386" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11245641">Wu et al. (2001)</a> found that the ala455/ala455 (AA) genotype was significantly more prevalent in controls compared to patients (p = 0.016). The prevalence of the AA genotype in black and white controls was 93% and 67%, respectively (p = 0.018). Statistical analysis indicated that having the val455 allele increased the risk of coronary heart disease by 6.1-fold in blacks, but not in whites. There was no association between this SNP and soluble THBD. <a href="#26" class="mim-tip-reference" title="Wu, K. K., Aleksic, N., Ahn, C., Boerwinkle, E., Folsom, A. R., Juneja, H. <strong>Thrombomodulin ala455val polymorphism and risk of coronary heart disease.</strong> Circulation 103: 1386-1389, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11245641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11245641</a>] [<a href="https://doi.org/10.1161/01.cir.103.10.1386" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11245641">Wu et al. (2001)</a> noted that their results conflicted with those of <a href="#19" class="mim-tip-reference" title="Norlund, L., Holm, J., Zoller, B., Ohlin, A.-K. <strong>A common thrombomodulin amino acid dimorphism is associated with myocardial infarction.</strong> Thromb. Haemost. 77: 248-251, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9157575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9157575</a>]" pmid="9157575">Norlund et al. (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11245641+9157575" 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="Faioni, E. M., Franchi, F., Castaman, G., Biguzzi, E., Rodeghiero, F. <strong>Mutations in the thrombomodulin gene are rare in patients with severe thrombophilia.</strong> Brit. J. Haemat. 118: 595-599, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12139752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12139752</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2002.03644.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12139752">Faioni et al. (2002)</a> found no association with venous thrombosis and the A455V polymorphism among 38 patients and controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12139752" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a cohort of 141 young women (44% black and 56% white; 15 to 44 years of age) with ischemic stroke and 210 controls (35% black), <a href="#2" class="mim-tip-reference" title="Cole, J. W., Roberts, S. C., Gallagher, M., Giles, W. H., Mitchell, B. D., Steinberg, K. K., Wozniak, M. A., Macko, R. F., Reinhart, L. J., Kittner, S. J. <strong>Thrombomodulin ala455val polymorphism and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study.</strong> BMC Neurol. 4: 21-27, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15574195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15574195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15574195[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/10.1186/1471-2377-4-21" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15574195">Cole et al. (2004)</a> found a significant association between stroke and the AA genotype compared to the AV or VV genotype (OR of 1.9). The AA genotype was more common among black than white controls (81% vs 68%), but there was no significant interaction between the risk genotype and race (OR of 2.7 for blacks and 1.6 for whites). The association was stronger when probable and possible causes of stroke were removed from the analysis. <a href="#2" class="mim-tip-reference" title="Cole, J. W., Roberts, S. C., Gallagher, M., Giles, W. H., Mitchell, B. D., Steinberg, K. K., Wozniak, M. A., Macko, R. F., Reinhart, L. J., Kittner, S. J. <strong>Thrombomodulin ala455val polymorphism and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study.</strong> BMC Neurol. 4: 21-27, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15574195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15574195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15574195[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/10.1186/1471-2377-4-21" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15574195">Cole et al. (2004)</a> concluded that the AA genotype is more prevalent among blacks than whites and is associated with increased risk of early-onset ischemic stroke. However, it was unclear whether this polymorphism was functionally related to thrombomodulin expression or whether the association was due to linkage to a nearby functional variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15574195" 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>.0009 THROMBOPHILIA DUE TO THROMBOMODULIN DEFECT</strong>
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THBD, ARG385SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122807 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122807;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=rs398122807" 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=rs398122807" 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 woman with recurrent deep venous thrombosis beginning at age 76 who had a myocardial infarction at age 90, <a href="#14" class="mim-tip-reference" title="Kunz, G., Ohlin, A.-K., Adami, A., Zoller, B., Svensson, P., Lane, D. A. <strong>Naturally occurring mutations in the thrombomodulin gene leading to impaired expression and function.</strong> Blood 99: 3646-3653, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11986219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11986219</a>] [<a href="https://doi.org/10.1182/blood.v99.10.3646" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11986219">Kunz et al. (2002)</a> identified a heterozygous 1209G-T transversion in the THBD gene, resulting in an arg385-to-ser (R385S) substitution in the last amino acid in the fourth EGF-like domain, which is important for efficient protein C activation. In vitro functional expression studies showed that the mutant protein had reduced expression (50% compared to wildtype), as well as significantly decreased cofactor activity with increased Km values for protein C activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11986219" 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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THBD, -151G-T (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs16984852;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs16984852</a>)
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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> rs16984852 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs16984852;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/rs16984852?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=rs16984852" 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=rs16984852" 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=RCV000128419 OR RCV001142106 OR RCV002055839 OR RCV002247504 OR RCV004751276" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000128419, RCV001142106, RCV002055839, RCV002247504, RCV004751276" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000128419...</a>
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<p><a href="#24" class="mim-tip-reference" title="Tang, L., Wang, H.-F., Lu, X., Jian, X.-R., Jin, B., Zheng, H., Li, Y.-Q., Wang, Q.-Y., Wu, T.-C., Guo, H., Liu, H., Guo, T., Yu, J.-M., Yang, R., Yang, Y., Hu, Y. <strong>Common genetic risk factors for venous thrombosis in the Chinese population.</strong> Am. J. Hum. Genet. 92: 177-187, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23332921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23332921</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23332921[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23332921">Tang et al. (2013)</a> demonstrated that the -151G-T variant in the 5-prime UTR of the THBD gene significantly reduced gene expression and caused a predisposition to venous thrombosis (THPH12; <a href="/entry/614486">614486</a>). In a case-control study, heterozygotes had a 2.80-fold (95% confidence interval = 1.88-4.29) increased risk of venous thrombosis. In a family analysis involving 176 first-degree relatives from 38 index families, <a href="#24" class="mim-tip-reference" title="Tang, L., Wang, H.-F., Lu, X., Jian, X.-R., Jin, B., Zheng, H., Li, Y.-Q., Wang, Q.-Y., Wu, T.-C., Guo, H., Liu, H., Guo, T., Yu, J.-M., Yang, R., Yang, Y., Hu, Y. <strong>Common genetic risk factors for venous thrombosis in the Chinese population.</strong> Am. J. Hum. Genet. 92: 177-187, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23332921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23332921</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23332921[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23332921">Tang et al. (2013)</a> showed that first-degree relatives with this variant had a 3.42-fold increased risk of venous thrombosis; their probability of remaining thrombosis-free was significantly lower than that of relatives without the variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23332921" 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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Anastasiou, G., Gialeraki, A., Merkouri, E., Politou, M., Travlou, A.
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<strong>Thrombomodulin as a regulator of the anticoagulant pathway: implication in the development of thrombosis.</strong>
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Blood Coagul. Fibrinolysis 23: 1-10, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036808</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22036808" 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/10.1097/MBC.0b013e32834cb271" target="_blank">Full Text</a>]
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Cole, J. W., Roberts, S. C., Gallagher, M., Giles, W. H., Mitchell, B. D., Steinberg, K. K., Wozniak, M. A., Macko, R. F., Reinhart, L. J., Kittner, S. J.
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<strong>Thrombomodulin ala455val polymorphism and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study.</strong>
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BMC Neurol. 4: 21-27, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15574195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15574195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15574195[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=15574195" 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/10.1186/1471-2377-4-21" target="_blank">Full Text</a>]
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Delvaeye, M., Noris, M., De Vriese, A., Esmon, C. T., Esmon, N. L., Ferrell, G., Del-Favero, J., Plaisance, S., Claes, B., Lambrechts, D., Zoja, C., Remuzzi, G., Conway, E. M.
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<strong>Thrombomodulin mutations in atypical hemolytic-uremic syndrome.</strong>
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New Eng. J. Med. 361: 345-357, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19625716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19625716</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19625716[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=19625716" 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/10.1056/NEJMoa0810739" target="_blank">Full Text</a>]
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Doggen, C. J. M., Kunz, G., Rosendaal, F. R., Lane, D. A., Vos, H. L., Stubbs, P. J., Cats, V. M., Ireland, H.
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<strong>A mutation in the thrombomodulin gene, 127G to A coding for ala25-to-thr, and the risk of myocardial infarction in men.</strong>
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Thromb. Haemost. 80: 743-748, 1998.
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[<a href="https://doi.org/10.1055/s-2007-1003522" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0888-7543(89)90038-4" target="_blank">Full Text</a>]
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<strong>Mutations in the thrombomodulin gene are rare in patients with severe thrombophilia.</strong>
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[<a href="https://doi.org/10.1046/j.1365-2141.2002.03644.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1046/j.1365-2141.2001.02964.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.cir.96.1.15" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nm825" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.84.18.6425" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1182/blood.v99.10.3646" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.atv.19.4.1098" target="_blank">Full Text</a>]
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<strong>Pericardial mesothelioma secreting thrombomodulin.</strong>
|
|
Am. Heart J. 132: 1309-1311, 1996.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8969598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8969598</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8969598" 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/s0002-8703(96)90490-1" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Takeda2007" class="mim-anchor"></a>
|
|
<div class="">
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<p class="mim-text-font">
|
|
Takeda, N., Maemura, K., Horie, S., Oishi, K., Imai, Y., Harada, T., Saito, T., Shiga, T., Amiya, E., Manabe, I., Ishida, N., Nagai, R.
|
|
<strong>Thrombomodulin is a clock-controlled gene in vascular endothelial cells.</strong>
|
|
J. Biol. Chem. 282: 32561-32567, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17848551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17848551</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17848551" 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/10.1074/jbc.M705692200" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Tang2013" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
Tang, L., Wang, H.-F., Lu, X., Jian, X.-R., Jin, B., Zheng, H., Li, Y.-Q., Wang, Q.-Y., Wu, T.-C., Guo, H., Liu, H., Guo, T., Yu, J.-M., Yang, R., Yang, Y., Hu, Y.
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<strong>Common genetic risk factors for venous thrombosis in the Chinese population.</strong>
|
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Am. J. Hum. Genet. 92: 177-187, 2013.
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|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23332921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23332921</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23332921[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=23332921" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2012.12.013" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="Wen1987" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Wen, D., Dittman, W. A., Ye, R. D., Deaven, L. L., Majerus, P. W., Sadler, J. E.
|
|
<strong>Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene.</strong>
|
|
Biochemistry 26: 4350-4357, 1987.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2822087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2822087</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2822087" 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/10.1021/bi00388a025" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Wu2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wu, K. K., Aleksic, N., Ahn, C., Boerwinkle, E., Folsom, A. R., Juneja, H.
|
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<strong>Thrombomodulin ala455val polymorphism and risk of coronary heart disease.</strong>
|
|
Circulation 103: 1386-1389, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11245641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11245641</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11245641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/01.cir.103.10.1386" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Yasuda1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yasuda, K., Espinosa, R., III, Davis, E. M., Le Beau, M. M., Bell, G. I.
|
|
<strong>Human somatostatin receptor genes: localization of SSTR5 to human chromosome 20p11.2.</strong>
|
|
Genomics 17: 785-786, 1993.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8244401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8244401</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8244401" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1993.1410" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="28" class="mim-anchor"></a>
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<a id="Ziegler-Heitbrock2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ziegler-Heitbrock, L., Ancuta, P., Crowe, S., Dalod, M., Grau, V., Hart, D. N., Leenen, P. J. M., Liu, Y.-J., MacPherson, G., Randolph, G. J., Scherberich, J., Schmitz, J., Shortman, K., Sozzani, S., Strobl, H., Zembala, M., Austyn, J. M., Lutz, M. B.
|
|
<strong>Nomenclature of monocytes and dendritic cells in blood.</strong>
|
|
Blood 116: e74-e80, 2010. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20628149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20628149</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20628149" 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/10.1182/blood-2010-02-258558" 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 : 6/25/2014
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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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Cassandra L. Kniffin - updated : 2/23/2012<br>Paul J. Converse - updated : 7/15/2011<br>Cassandra L. Kniffin - updated : 7/27/2009<br>Ada Hamosh - updated : 2/27/2003<br>Victor A. McKusick - updated : 10/16/2002<br>Victor A. McKusick - updated : 12/5/2001<br>Victor A. McKusick - updated : 11/9/2001<br>Victor A. McKusick - updated : 2/3/1999<br>Victor A. McKusick - updated : 2/18/1997
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 9/2/1987
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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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alopez : 12/12/2017
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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 : 09/01/2016<br>carol : 09/23/2014<br>alopez : 6/25/2014<br>carol : 12/19/2013<br>carol : 1/7/2013<br>terry : 3/12/2012<br>carol : 3/7/2012<br>mgross : 3/2/2012<br>carol : 3/1/2012<br>carol : 2/28/2012<br>terry : 2/28/2012<br>carol : 2/28/2012<br>ckniffin : 2/23/2012<br>carol : 11/23/2011<br>terry : 11/4/2011<br>mgross : 7/15/2011<br>mgross : 7/15/2011<br>carol : 7/15/2011<br>carol : 4/11/2011<br>ckniffin : 4/8/2011<br>carol : 4/7/2011<br>carol : 7/30/2009<br>ckniffin : 7/27/2009<br>carol : 10/21/2008<br>carol : 10/9/2008<br>carol : 10/8/2008<br>alopez : 12/1/2006<br>wwang : 11/8/2006<br>mgross : 3/17/2004<br>alopez : 3/4/2003<br>alopez : 3/4/2003<br>terry : 2/27/2003<br>tkritzer : 11/19/2002<br>tkritzer : 11/4/2002<br>tkritzer : 10/22/2002<br>tkritzer : 10/22/2002<br>terry : 10/16/2002<br>ckniffin : 6/5/2002<br>alopez : 12/11/2001<br>terry : 12/5/2001<br>carol : 11/28/2001<br>mcapotos : 11/26/2001<br>terry : 11/9/2001<br>alopez : 2/3/2000<br>carol : 2/11/1999<br>terry : 2/3/1999<br>jenny : 2/18/1997<br>terry : 2/12/1997<br>terry : 6/14/1996<br>terry : 6/11/1996<br>carol : 2/20/1995<br>carol : 9/21/1993<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>carol : 12/18/1989<br>carol : 12/12/1989
|
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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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</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>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 188040
|
|
</span>
|
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</h3>
|
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</div>
|
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<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
THROMBOMODULIN; THBD
|
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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>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
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</span>
|
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</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
THRM<br />
|
|
CD141 ANTIGEN; CD141
|
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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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: THBD</em></strong>
|
|
</span>
|
|
</p>
|
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</div>
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<div>
|
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<p>
|
|
<span class="mim-text-font">
|
|
|
|
<strong>SNOMEDCT:</strong> 1197595004;
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
|
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<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 20p11.21
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 20:23,045,633-23,049,672 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
|
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|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
20p11.21
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Hemolytic uremic syndrome, atypical, susceptibility to, 6}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
612926
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
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</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Thrombophilia 12 due to thrombomodulin defect
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
614486
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
|
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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">
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<p>The THBD gene encodes thrombomodulin, an endothelial cell surface glycoprotein that forms a 1:1 complex with the coagulation factor thrombin (F2; 176930). Binding of thrombin to this high-affinity receptor alters its specificity toward several substrates, ultimately acting as an antithrombotic factor. The F2:THBD complex activates protein C (PROC; 612283) approximately 1,000 times faster than thrombin alone, and activated protein C degrades clotting factors V (F5; 612309) and VIII (F8; 300841). In addition, THBD can inhibit procoagulant functions of thrombin, such as platelet activation or fibrinogen clotting. THBD can also promote antithrombin III (SERPINC1; 107300) inhibition of thrombin. Thus, thrombomodulin converts thrombin into a physiologic anticoagulant (summary by Esmon (1987) and Anastasiou et al., 2012). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Wen et al. (1987) presented the complete cDNA sequence of human thrombomodulin. The sequence encodes a 60.3-kD protein of 575 amino acids. The predicted protein sequence includes a signal peptide of about 21 amino acids, an amino terminal ligand-binding domain of about 223 amino acids, an epidermal growth factor (EGF) homology region (see 131530) of 236 amino acids, a serine/threonine-rich segment of 34 amino acids, a membrane-spanning domain of 23 amino acids, and a cytoplasmic tail of 38 amino acids. The EGF homology region consists of 6 tandemly repeated EGF-like domains. The organization of thrombomodulin is similar to that of LDL receptor (606945), and the protein is homologous to a large number of other proteins that also contain EGF-like domains, including factor VII (613878), factor IX (300746), factor X (613872), factor XII (610619), protein C, tissue plasminogen activator (173370), and urokinase (191840). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Jackman et al. (1987) reviewed the structure of the thrombomodulin gene and commented on the lack of introns. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By molecular hybridization to sorted chromosomes, Wen et al. (1987) localized the structural gene for thrombomodulin to chromosome 20. By in situ hybridization, Espinosa et al. (1989) localized the THBD gene to 20p12-cen. By FISH, Yasuda et al. (1993) assigned the THBD gene to 20p11, proximal to NEC2 (162151) and SSTR5 (182455) which are located at 20p11.2. By radiation hybrid mapping, Maglott et al. (1996) localized the THBD gene to a region corresponding to 20p11.2. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ishii and Majerus (1985) demonstrated thrombomodulin in human plasma and urine. The physiologic significance of circulating and urinary thrombomodulin was obscure. </p><p>Malignant primary tumors of the pericardium such as primary pericardial mesothelioma are very rare. Thrombomodulin has been identified on the pleural mesothelioma cells. Okura et al. (1996) described the case of a 25-year-old man who was found to have a pericardial mesothelioma secreting thrombomodulin. Very little clot formation in the pericardial space may have been the result of the anticoagulant effect of thrombomodulin. </p><p>Using microarray technology to identify CLOCK (601851)-controlled genes in human and murine vascular endothelial cells, Takeda et al. (2007) found that thrombomodulin was upregulated by CLOCK in these cells. Thbd mRNA and protein showed a clear circadian oscillation in murine heart and lung. A heterodimer of CLOCK and BMAL2 (ARNTL2; 614517) bound directly to the E-box of the THBD promoter, resulting in activation. The phase of circadian oscillation of Thbd mRNA expression was altered by temporal feeding restriction in mice, suggesting that gene expression is regulated by the peripheral clock system. In addition, this circadian oscillation of Thbd was not seen in Clock mutant mice. The data suggested that there is a peripheral clock in vascular endothelial cells that regulates THBD gene expression, and that the oscillation of this expression may contribute to the circadian variation of cardiovascular events. </p><p>In in vitro cellular studies, Delvaeye et al. (2009) demonstrated that thrombomodulin binds to C3b (see 120700) and factor H (CFH; 134370) and negatively regulates complement by accelerating factor I (CFI; 217030)-mediated inactivation of C3b in the presence of cofactors. By promoting activation of the plasma procarboxypeptidase B (CPB2; 603101), thrombomodulin also accelerates the inactivation of anaphylatoxins C3a and C5a. Thus, thrombomodulin provides protection against complement activation. </p><p>As part of an effort to clarify the nomenclature for monocytes and dendritic cells (DCs) in blood, Ziegler-Heitbrock et al. (2010) reported that CD141 is a marker for 1 of 2 types of myeloid DCs. CD141-positive myeloid DCs represent an immature or precursor stage of circulating DCs. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Thrombophilia Due to Thrombomodulin Defect</em></strong></p><p>
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The role of thrombomodulin in thrombosis (THPH12; 614486) is controversial. Although there have been several reports of THBD mutations in patients with venous thrombosis, clear functional evidence for the pathogenicity of these mutations is lacking. In a review, Anastasiou et al. (2012) noted that thrombomodulin has a major role in capillary beds and that THBD variation may not be associated with large vessel thrombosis. It is likely that genetic or environmental risk factors in addition to THBD variation are involved in the pathogenesis of venous thrombosis. However, variation in the THBD gene may be associated with increased risk for arterial thrombosis and myocardial infarction. This association may be attributed to the fact that thrombomodulin modulates inflammatory processes, complement activity, and fibrinolysis. </p><p>Late fetal loss can be associated with placental insufficiency and coagulation defects. Thrombomodulin and the endothelial protein C receptor (EPCR; 600646) are glycoprotein receptors expressed mainly on the endothelial surface of blood vessels and also in the placenta; they both play a key physiologic role in the protein C anticoagulant pathway. Franchi et al. (2001) investigated the possibility that defects in these proteins play an important role in the pathogenesis of late fetal loss. They performed a case-control study in 95 women with unexplained late fetal loss (after 20 weeks); the control group comprised 236 women who had given birth to at least 1 healthy baby and had no history of late fetal loss or obstetrical complications. In the 95 patients, they found 5 mutations in the THBD gene and 2 in the EPCR gene; in the 236 control subjects, they found 3 mutations in the THBD gene and 1 in the EPCR gene. The relative risk for late fetal loss for carriers of mutation in either the THBD or EPCR gene was estimated by an odds ratio of 4.0. </p><p>To evaluate the contribution of THBD gene mutations to venous thrombosis, Faioni et al. (2002) examined 38 patients with recurrent, documented thrombotic events at a young age and a positive family history. Twelve individuals with low levels of soluble thrombomodulin in plasma were also studied. Two mutations were identified: -33G-A (188040.0004), in a severely thrombophilic patient, and D468Y (188040.0001). The allelic frequency of an ala455-to-val polymorphism (A455V; 188040.0008) was identical in patients and controls. Faioni et al. (2002) concluded that mutations in the THBD gene are a very rare cause of severe thrombophilia. </p><p>Tang et al. (2013) studied venous thrombosis in the Chinese population, examining 1,304 individuals diagnosed with a first venous thrombosis and 1,334 age- and sex-matched healthy participants. Resequencing of THBD in 60 individuals with venous thrombosis and in 60 controls, and a functional assay, showed that a common variant, c.-151G-T (188040.0010), in the 5-prime UTR significantly reduced the gene expression and could cause a predisposition to venous thrombosis. This variant was then genotyped in a case-control study, and results indicated that heterozygotes had a 2.80-fold (95% confidence interval = 1.88-4.29) increased risk of venous thrombosis. The THBD c.-151G-T variant was further investigated in a family analysis involving 176 first-degree relatives from 38 index families. First-degree relatives with this variant had a 3.42-fold increased risk of venous thrombosis, and their probability of remaining thrombosis-free was significantly lower than that of relatives without the variant. In addition, 5 rare mutations that might be deleterious were also identified in thrombophilic individuals by sequencing. </p><p><strong><em>Susceptibility to Atypical Hemolytic Uremic Syndrome 6</em></strong></p><p>
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In 7 (4.6%) of 153 patients with atypical hemolytic uremic syndrome (AHUS6; 612926), Delvaeye et al. (2009) identified 6 different heterozygous mutations in the THBD gene (see, e.g., 188040.0005-188040.0007). In vitro functional expression studies showed that cells transfected with mutant THBD were less effective in converting C3b to iC3b on the cell surface after complement activation, and were thus not as well protected against complement activation. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Isermann et al. (2003) found that disruption of the mouse thrombomodulin gene leads to embryonic lethality caused by a defect in the placenta. They showed that the abortion of thrombomodulin-deficient embryos is caused by tissue factor (134390)-initiated activation of the blood coagulation cascade at the fetomaternal interface. Activated coagulation factors induced cell death and growth inhibition of placental trophoblast cells by 2 distinct mechanisms. The death of giant trophoblast cells was caused by the conversion of fibrinogen to fibrin (see 134820) and subsequent formation of fibrin degradation products. In contrast, the growth arrest of trophoblast cells is not mediated by fibrin, but is a likely result of engagement of the protease-activated receptors PAR2 (600933) and PAR4 (602779) by coagulation factors. Isermann et al. (2003) concluded that their findings show a novel function for the thrombomodulin-protein C system in controlling the growth and survival of trophoblast cells in the placenta. This function is essential for the maintenance of pregnancy. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>10 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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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THBD, ASP468TYR
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<br />
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SNP: rs41348347,
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gnomAD: rs41348347,
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ClinVar: RCV000013551, RCV000263795, RCV000949435, RCV001818153, RCV002293979, RCV003924830
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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>This variant, formerly titled THROMBOPHILIA DUE TO THROMBOMODULIN DEFECT (614486), has been reclassified based on the findings of Nakazawa et al. (1999) and Kunz et al. (2002). </p><p>In a 45-year-old Hispanic man who developed a pulmonary embolism, Ohlin and Marlar (1995) identified a heterozygous 1456G-T transversion in the THBD gene, resulting in an asp468-to-tyr (D468Y) substitution between the transmembrane domain and the sixth EGF-like domain. He had decreased soluble THBD fragments in serum compared to controls. The patient's mother died suddenly, apparently of pulmonary embolus; his 23-year-old son, who had no history of thrombosis, was heterozygous for the mutation. </p><p>Nakazawa et al. (1999) demonstrated that the D468Y variant protein was expressed normally at the cell surface in COS-7 cells and had normal cofactor activity for activation of protein C. In addition, the Km and Vmax of the variant protein were similar to wildtype, casting doubt on its pathogenicity. </p><p>Faioni et al. (2002) identified a heterozygous D468Y substitution in 1 of 12 patients with thrombophilia and low serum THBD levels. The patient was a 52-year-old woman with deep vein thrombosis of the lower limb and a stroke. However, Faioni et al. (2002) noted that there is no evidence to support the frequent involvement of THBD mutations in large vessel thrombosis, if at all, and suggested that THBD defects be sought only for research purposes. </p><p>Kunz et al. (2002) found no abnormality in cell surface expression or thrombomodulin cofactor function in studies of the D468Y protein. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 THROMBOPHILIA DUE TO THROMBOMODULIN DEFECT</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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THBD, ALA25THR
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<br />
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SNP: rs2122673257,
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ClinVar: RCV000013552
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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 unrelated patients with thrombophilia due to thrombomodulin defect (614486), Doggen et al. (1998) identified a heterozygous 127G-A mutation in the THBD gene, resulting in an ala25-to-thr (A25T) substitution. The patients were ascertained from a larger cohort of 104 patients with myocardial infarction. In a larger study of 560 men with a first myocardial infarction before the age of 70, Doggen et al. (1998) found that 12 were carriers of the A25T substitution. In a control group of 646 men, frequency-matched for age, 7 were carriers of the A25T substitution. The allelic frequencies were 1.07% among patients and 0.54% among controls, suggesting an odds ratio of 2.0. In patients below age 50, the predicted risk was almost 7 times increased (odds ratio, 6.5). In the presence of smoking or a metabolic risk factor, the predicted risk increased to 9-fold and 4-fold, respectively. </p><p>In a 42-year-old Swedish woman with thrombophilia due to thrombomodulin defect who developed a sagittal sinus thrombosis causing neurologic symptoms, Norlund et al. (1997) identified a heterozygous A25T mutation. She had been taking oral contraceptives for 18 years. Her unaffected 16-year-old daughter also carried the mutation. The substitution is located in a conserved residue in the N terminal, lectin-like extracellular domain of the protein, which may be involved in regulation of cell surface expression of the protein. </p><p>Kunz et al. (2002) found no abnormality in cell surface expression or thrombomodulin cofactor function in studies of the A25T protein. </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 THROMBOPHILIA DUE TO THROMBOMODULIN DEFECT</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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THBD, 1-BP INS, 1689T
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<br />
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ClinVar: RCV000013553
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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 man with thrombophilia due to thrombomodulin defect (614486) resulting in an occlusive myocardial infarction at age 52 years, Kunz et al. (2000) found a heterozygous frameshift insertion mutation, 1689insT, in the THBD gene. The mutation predicts an elongated gene product because of substitution of the last 12 C-terminal amino acids by 61 abnormal residues. Pedigree analysis suggested that a brother who had suffered a fatal myocardial infarction probably also carried the mutation. Known risk factors for myocardial infarction, including smoking, increased blood pressure, elevated triglycerides, and elevated cholesterol, were present in the proband and other family members. Carriers of the mutant allele expressed significantly lower amounts of thrombomodulin on the surface of their monocytes and lower levels of soluble thrombomodulin in plasma. Transfection of the mutation in COS-7 cells resulted in reduced cell surface expression of mutant THBD associated with impaired translocation through the endoplasmic reticulum/Golgi apparatus compared to wildtype. In addition, cells expressing abnormal thrombomodulin had a 2.5-fold reduced ability to accelerate the thrombin (F2; 176930)-mediated activation of protein C (PROC; 612283). </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 THROMBOPHILIA DUE TO THROMBOMODULIN DEFECT</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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THBD, -33G-A, PROMOTER
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<br />
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SNP: rs13306848,
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gnomAD: rs13306848,
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ClinVar: RCV001724979, RCV001810751
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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>Ireland et al. (1997) identified a heterozygous -33G-A transition in the promoter region of the THBD gene adjacent to the TATA in 1 of 104 patients with myocardial infarction (614486) and in 1 control. Both individuals were of Asian origin. </p><p>Le Flem et al. (1999) identified a heterozygous -33G-A transition in the THBD gene in 2 (0.97%) of 205 patients with venous thromboembolic disease and in 1 (0.25%) of 394 controls, suggesting that it may be a risk factor. However, in vitro functional expression assays indicated that the -33G-A change caused only a mild decrease in promoter activity, suggesting that it may not be a risk factor for venous thrombosis by lowering the expression of THBD. </p><p>Among 320 Chinese patients with coronary artery disease and 200 matched controls, Li et al. (2000) found a significant association between the -33G-A variant and disease. The GA and AA genotypes were found in 23.8% of patients compared to 15.5% of controls (OR of 1.70, p = 0.031). The soluble thrombomodulin level was significantly higher in patients compared to controls, was higher in patients with the GG genotype compared to those with the GA or AA genotype, and increased with more severe disease in those with the GG genotype, but not in those with the GA or AA genotype. </p><p>Faioni et al. (2002) examined 38 patients with recurrent, documented thrombotic events at a young age and a positive family history. One patient with thrombophilia was found to have a heterozygous -33G-A transition (also known as -201G-A in another numbering system) in the promoter region of the THBD gene. This patient had a deep venous thrombosis of a lower limb at age 39 years, followed by 3 recurrent events at age 40, including a pulmonary embolism. </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 HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 6</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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THBD, ALA43THR
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<br />
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SNP: rs1800576,
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gnomAD: rs1800576,
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ClinVar: RCV000013555, RCV000886689, RCV001328105, RCV001818154, RCV003914835
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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 24-year-old man with recurrent AHUS6 (612926) since age 1 year, Delvaeye et al. (2009) identified a heterozygous mutation in the THBD gene, resulting in an ala43-to-thr (A43T) substitution in the lectin-like domain of the protein. He had had several episodes of aHUS in infancy, leading to chronic renal failure. Serum C3 (120700) was decreased, consistent with activation of the alternative complement pathway. He had 8 sibs, 3 of whom had died during acute episodes of aHUS. A sister, who also carried the A43T mutation, had had 1 aHUS episode during infancy. The unaffected mother and another unaffected sib were also heterozygous carriers. In vitro functional expression studies showed that cells transfected with mutant THBD were less effective in converting C3b to iC3b on the cell surface after complement activation, and were thus not as well protected against complement activation. </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 HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 6</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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THBD, ASP53GLY
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<br />
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SNP: rs121918667,
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gnomAD: rs121918667,
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ClinVar: RCV000013556
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a boy with AHUS6 (612926), Delvaeye et al. (2009) identified a heterozygous mutation in the THBD gene, resulting in an asp53-to-gly (D53G) substitution in the lectin-like domain of the protein. He had recurrent episodes since age 6 months and 1 sib who had died of aHUS. The unaffected mother and an unaffected brother also carried the mutation. In vitro functional expression studies showed that cells transfected with mutant THBD were less effective in converting C3b to iC3b on the cell surface after complement activation, and were thus not as well protected against complement activation. </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 HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 6</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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THBD, PRO495SER
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<br />
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SNP: rs1800578,
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gnomAD: rs1800578,
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ClinVar: RCV000013557, RCV000899504, RCV001328104, RCV003313772, RCV003944819
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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 girl with recurrent AHUS6 (612926) since childhood and residual renal dysfunction, Delvaeye et al. (2009) identified a heterozygous mutation in the THBD gene, resulting in a pro495-to-ser (P495S) substitution in the serine-threonine-rich region of the protein. Serum C3 (120700) was decreased. In vitro functional expression studies showed that cells transfected with mutant THBD were less effective in converting C3b to iC3b on the cell surface after complement activation, and were thus not as well protected against complement activation. </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>.0008 VARIANT OF UNKNOWN SIGNIFICANCE</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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THBD, ALA455VAL
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<br />
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SNP: rs1042579,
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gnomAD: rs1042579,
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ClinVar: RCV000302594, RCV001516722, RCV001643035, RCV002294300, RCV003969973
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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>This common polymorphism in the THBD gene, a 1418C-T transition resulting in an ala455-to-val (A455V) substitution in the sixth EGF-like domain in the thrombin-binding domain (Cole et al., 2004), is classified as a variant of unknown significance because there are conflicting reports about its role in thrombophilia and myocardial infarction. </p><p>Norlund et al. (1997) found an association between the A455V substitution in the THBD gene and the development of premature myocardial infarction (MI). Among 97 MI survivors and 159 controls, the C allele (ala455) was significantly more frequent among patients than controls (0.82 compared to 0.72; p = 0.035). Norlund et al. (1997) suggested that the A455V substitution may affect the function of thrombomodulin and activation of the protein C anticoagulant pathway. </p><p>Among 104 patients with MI who had no history of thrombotic episodes and 104 controls, Ireland et al. (1997) found no association between disease and the A455V variant. </p><p>In a cohort of 376 patients (23% black, 77% white) with coronary heart disease, including MI, and 461 controls, Wu et al. (2001) found that the ala455/ala455 (AA) genotype was significantly more prevalent in controls compared to patients (p = 0.016). The prevalence of the AA genotype in black and white controls was 93% and 67%, respectively (p = 0.018). Statistical analysis indicated that having the val455 allele increased the risk of coronary heart disease by 6.1-fold in blacks, but not in whites. There was no association between this SNP and soluble THBD. Wu et al. (2001) noted that their results conflicted with those of Norlund et al. (1997). </p><p>Faioni et al. (2002) found no association with venous thrombosis and the A455V polymorphism among 38 patients and controls. </p><p>In a cohort of 141 young women (44% black and 56% white; 15 to 44 years of age) with ischemic stroke and 210 controls (35% black), Cole et al. (2004) found a significant association between stroke and the AA genotype compared to the AV or VV genotype (OR of 1.9). The AA genotype was more common among black than white controls (81% vs 68%), but there was no significant interaction between the risk genotype and race (OR of 2.7 for blacks and 1.6 for whites). The association was stronger when probable and possible causes of stroke were removed from the analysis. Cole et al. (2004) concluded that the AA genotype is more prevalent among blacks than whites and is associated with increased risk of early-onset ischemic stroke. However, it was unclear whether this polymorphism was functionally related to thrombomodulin expression or whether the association was due to linkage to a nearby functional variant. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0009 THROMBOPHILIA DUE TO THROMBOMODULIN DEFECT</strong>
|
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</span>
|
|
</h4>
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</div>
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<div>
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<span class="mim-text-font">
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THBD, ARG385SER
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<br />
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SNP: rs398122807,
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ClinVar: RCV000022787, RCV005089299
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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 woman with recurrent deep venous thrombosis beginning at age 76 who had a myocardial infarction at age 90, Kunz et al. (2002) identified a heterozygous 1209G-T transversion in the THBD gene, resulting in an arg385-to-ser (R385S) substitution in the last amino acid in the fourth EGF-like domain, which is important for efficient protein C activation. In vitro functional expression studies showed that the mutant protein had reduced expression (50% compared to wildtype), as well as significantly decreased cofactor activity with increased Km values for protein C activation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 THROMBOPHILIA DUE TO THROMBOMODULIN DEFECT</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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THBD, -151G-T ({dbSNP rs16984852})
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<br />
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SNP: rs16984852,
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gnomAD: rs16984852,
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|
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ClinVar: RCV000128419, RCV001142106, RCV002055839, RCV002247504, RCV004751276
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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>Tang et al. (2013) demonstrated that the -151G-T variant in the 5-prime UTR of the THBD gene significantly reduced gene expression and caused a predisposition to venous thrombosis (THPH12; 614486). In a case-control study, heterozygotes had a 2.80-fold (95% confidence interval = 1.88-4.29) increased risk of venous thrombosis. In a family analysis involving 176 first-degree relatives from 38 index families, Tang et al. (2013) showed that first-degree relatives with this variant had a 3.42-fold increased risk of venous thrombosis; their probability of remaining thrombosis-free was significantly lower than that of relatives without the variant. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
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<p />
|
|
</div>
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<div>
|
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<ol>
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<li>
|
|
<p class="mim-text-font">
|
|
Anastasiou, G., Gialeraki, A., Merkouri, E., Politou, M., Travlou, A.
|
|
<strong>Thrombomodulin as a regulator of the anticoagulant pathway: implication in the development of thrombosis.</strong>
|
|
Blood Coagul. Fibrinolysis 23: 1-10, 2012.
|
|
|
|
|
|
[PubMed: 22036808]
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[Full Text: https://doi.org/10.1097/MBC.0b013e32834cb271]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Cole, J. W., Roberts, S. C., Gallagher, M., Giles, W. H., Mitchell, B. D., Steinberg, K. K., Wozniak, M. A., Macko, R. F., Reinhart, L. J., Kittner, S. J.
|
|
<strong>Thrombomodulin ala455val polymorphism and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study.</strong>
|
|
BMC Neurol. 4: 21-27, 2004.
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|
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|
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[PubMed: 15574195]
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[Full Text: https://doi.org/10.1186/1471-2377-4-21]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Delvaeye, M., Noris, M., De Vriese, A., Esmon, C. T., Esmon, N. L., Ferrell, G., Del-Favero, J., Plaisance, S., Claes, B., Lambrechts, D., Zoja, C., Remuzzi, G., Conway, E. M.
|
|
<strong>Thrombomodulin mutations in atypical hemolytic-uremic syndrome.</strong>
|
|
New Eng. J. Med. 361: 345-357, 2009.
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[PubMed: 19625716]
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[Full Text: https://doi.org/10.1056/NEJMoa0810739]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Doggen, C. J. M., Kunz, G., Rosendaal, F. R., Lane, D. A., Vos, H. L., Stubbs, P. J., Cats, V. M., Ireland, H.
|
|
<strong>A mutation in the thrombomodulin gene, 127G to A coding for ala25-to-thr, and the risk of myocardial infarction in men.</strong>
|
|
Thromb. Haemost. 80: 743-748, 1998.
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[PubMed: 9843165]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Esmon, N. L.
|
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<strong>Thrombomodulin.</strong>
|
|
Semin. Thromb. Hemost. 13: 454-463, 1987.
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[PubMed: 2827310]
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[Full Text: https://doi.org/10.1055/s-2007-1003522]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Espinosa, R., III, Sadler, J. E., Le Beau, M. M.
|
|
<strong>Regional localization of the human thrombomodulin gene to 20p12-cen.</strong>
|
|
Genomics 5: 649-650, 1989.
|
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|
|
[PubMed: 2559025]
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[Full Text: https://doi.org/10.1016/0888-7543(89)90038-4]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Faioni, E. M., Franchi, F., Castaman, G., Biguzzi, E., Rodeghiero, F.
|
|
<strong>Mutations in the thrombomodulin gene are rare in patients with severe thrombophilia.</strong>
|
|
Brit. J. Haemat. 118: 595-599, 2002.
|
|
|
|
|
|
[PubMed: 12139752]
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[Full Text: https://doi.org/10.1046/j.1365-2141.2002.03644.x]
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Franchi, F., Biguzzi, E., Cetin, I., Facchetti, F., Radaelli, T., Bozzo, M., Pardi, G., Faioni, E. M.
|
|
<strong>Mutations in the thrombomodulin and endothelial protein C receptor genes in women with late fetal loss.</strong>
|
|
Brit. J. Haemat. 114: 641-646, 2001.
|
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|
|
[PubMed: 11552992]
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|
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[Full Text: https://doi.org/10.1046/j.1365-2141.2001.02964.x]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Ireland, H., Kunz, G., Kyriakoulis, K., Stubbs, P. J., Lane, D. A.
|
|
<strong>Thrombomodulin gene mutations associated with myocardial infarction.</strong>
|
|
Circulation 96: 15-18, 1997.
|
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|
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|
|
[PubMed: 9236408]
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[Full Text: https://doi.org/10.1161/01.cir.96.1.15]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Isermann, B., Sood, R., Pawlinski, R., Zogg, M., Kalloway, S., Degen, J. L., Mackman, N., Weiler, H.
|
|
<strong>The thrombomodulin-protein C system is essential for the maintenance of pregnancy.</strong>
|
|
Nature Med. 9: 331-337, 2003.
|
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|
[PubMed: 12579195]
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[Full Text: https://doi.org/10.1038/nm825]
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</p>
|
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</li>
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ishii, H., Majerus, P. W.
|
|
<strong>Thrombomodulin is present in human plasma and urine.</strong>
|
|
J. Clin. Invest. 76: 2178-2181, 1985.
|
|
|
|
|
|
[PubMed: 3001144]
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|
|
[Full Text: https://doi.org/10.1172/JCI112225]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Jackman, R. W., Beeler, D. L., Fritze, L., Soff, G., Rosenberg, R. D.
|
|
<strong>Human thrombomodulin gene is intron depleted: nucleic acid sequences of the cDNA and gene predict protein structure and suggest sites of regulatory control.</strong>
|
|
Proc. Nat. Acad. Sci. 84: 6425-6429, 1987.
|
|
|
|
|
|
[PubMed: 2819876]
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|
|
[Full Text: https://doi.org/10.1073/pnas.84.18.6425]
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Kunz, G., Ireland, H. A., Stubbs, P. J., Kahan, M., Coulton, G. C., Lane, D. A.
|
|
<strong>Identification and characterization of a thrombomodulin gene mutation coding for an elongated protein with reduced expression in a kindred with myocardial infarction.</strong>
|
|
Blood 95: 569-576, 2000.
|
|
|
|
|
|
[PubMed: 10627464]
|
|
|
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|
</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Kunz, G., Ohlin, A.-K., Adami, A., Zoller, B., Svensson, P., Lane, D. A.
|
|
<strong>Naturally occurring mutations in the thrombomodulin gene leading to impaired expression and function.</strong>
|
|
Blood 99: 3646-3653, 2002.
|
|
|
|
|
|
[PubMed: 11986219]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1182/blood.v99.10.3646]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Le Flem, L., Picard, V., Emmerich, J., Gandrille, S., Fiessinger, J.-N., Aiach, M., Alhenc-Gelas, M.
|
|
<strong>Mutations in promoter region of thrombomodulin and venous thromboembolic disease.</strong>
|
|
Arterioscler. Thromb. Vasc. Biol. 19: 1098-1104, 1999.
|
|
|
|
|
|
[PubMed: 10195941]
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|
|
[Full Text: https://doi.org/10.1161/01.atv.19.4.1098]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Li, Y.-H., Chen, J.-H., Wu, H.-L., Shi, G.-Y., Huang, H.-C., Chao, T.-H., Tsai, W.-C., Tsai, L.-M., Guo, H.-R., Wu, W.-S., Chen, Z.-C.
|
|
<strong>G-33A mutation in the promoter region of thrombomodulin gene and its association with coronary artery disease and plasma soluble thrombomodulin levels.</strong>
|
|
Am. J. Cardiol. 85: 8-12, 2000.
|
|
|
|
|
|
[PubMed: 11078228]
|
|
|
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|
|
[Full Text: https://doi.org/10.1016/s0002-9149(99)00597-4]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Maglott, D. R., Feldblyum, T. V., Durkin, A. S., Nierman, W. C.
|
|
<strong>Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p).</strong>
|
|
Mammalian Genome 7: 400-401, 1996.
|
|
|
|
|
|
[PubMed: 8661740]
|
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|
|
[Full Text: https://doi.org/10.1007/s003359900120]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Nakazawa, F., Koyama, T., Saito, T., Shibakura, M., Yoshinaga, H., Chung, D. H., Kamiyama, R., Hirosawa, S.
|
|
<strong>Thrombomodulin with the Asp468Tyr mutation is expressed on the cell surface with normal cofactor activity for protein C activation.</strong>
|
|
Brit. J. Haemat. 106: 416-420, 1999.
|
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|
|
[PubMed: 10460600]
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|
[Full Text: https://doi.org/10.1046/j.1365-2141.1999.01567.x]
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Norlund, L., Holm, J., Zoller, B., Ohlin, A.-K.
|
|
<strong>A common thrombomodulin amino acid dimorphism is associated with myocardial infarction.</strong>
|
|
Thromb. Haemost. 77: 248-251, 1997.
|
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|
|
|
[PubMed: 9157575]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Norlund, L., Zoller, B., Ohlin, A.-K.
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<strong>The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease.</strong>
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Okura, Y., Kato, K., Hanawa, H., Izumi, T., Kamishima, T., Yamato, Y., Emura, I., Shibata, A.
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<strong>Pericardial mesothelioma secreting thrombomodulin.</strong>
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Takeda, N., Maemura, K., Horie, S., Oishi, K., Imai, Y., Harada, T., Saito, T., Shiga, T., Amiya, E., Manabe, I., Ishida, N., Nagai, R.
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Tang, L., Wang, H.-F., Lu, X., Jian, X.-R., Jin, B., Zheng, H., Li, Y.-Q., Wang, Q.-Y., Wu, T.-C., Guo, H., Liu, H., Guo, T., Yu, J.-M., Yang, R., Yang, Y., Hu, Y.
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Yasuda, K., Espinosa, R., III, Davis, E. M., Le Beau, M. M., Bell, G. I.
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Ziegler-Heitbrock, L., Ancuta, P., Crowe, S., Dalod, M., Grau, V., Hart, D. N., Leenen, P. J. M., Liu, Y.-J., MacPherson, G., Randolph, G. J., Scherberich, J., Schmitz, J., Shortman, K., Sozzani, S., Strobl, H., Zembala, M., Austyn, J. M., Lutz, M. B.
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