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Entry
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- *176930 - COAGULATION FACTOR II; F2
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- OMIM
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<p>
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<span class="h4">*176930</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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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/176930">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div 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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<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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<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=ENSG00000180210;t=ENST00000311907" 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=2147" 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=176930" 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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<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=ENSG00000180210;t=ENST00000311907" 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_000506" 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_000506" 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=176930" 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=01488&isoform_id=01488_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/F2" 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/135807,190724,261695,339641,1335344,4503635,18653448,20136469,29243006,30802115,38018090,38018092,62897109,62897113,67624831,110623182,119588383,119588384,119588385,189066554,194373497,194383496,1347869440" 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/P00734" 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=2147" 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=ENSG00000180210;t=ENST00000311907" 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=F2" 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=F2" 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+2147" 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/F2" 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:2147" 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/2147" 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=chr11&hgg_gene=ENST00000311907.10&hgg_start=46719213&hgg_end=46739506&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:3535" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/f2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=176930[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=176930[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/ENSG00000180210" 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=F2" 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=F2" 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=F2" 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=F2&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/PA157" 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:3535" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:88380" 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/F2#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:88380" 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/2147/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=2147" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-4606" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
|
<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:176930" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<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:2147" 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=F2&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> 33297000<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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176930
|
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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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COAGULATION FACTOR II; F2
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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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
THROMBIN<br />
|
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PROTHROMBIN<br />
|
|
FACTOR II
|
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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">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=F2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">F2</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/11/351?start=-3&limit=10&highlight=351">11p11.2</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:46719213-46739506&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'})">11:46,719,213-46,739,506</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=614390,601367,613679,613679,188050" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="5">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/11/351?start=-3&limit=10&highlight=351">
|
|
11p11.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Pregnancy loss, recurrent, susceptibility to, 2}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/614390"> 614390 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
{Stroke, ischemic, susceptibility to}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/601367"> 601367 </a>
|
|
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/radial/176930" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>The F2 gene encodes coagulation factor II (<a href="https://enzyme.expasy.org/EC/3.4.21.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 3.4.21.5</a>), or prothrombin, a vitamin K-dependent glycoprotein synthesized in the liver as an inactive zymogen. Prothrombin is activated to the serine protease thrombin by factor Xa (F10; <a href="/entry/613872">613872</a>) in the presence of phospholipids, calcium, and factor Va (F5; <a href="/entry/612309">612309</a>). The activated thrombin enzyme plays an important role in hemostasis and thrombosis: it converts fibrinogen (<a href="/entry/134820">134820</a>) to fibrin for blood clot formation, stimulates platelet aggregation, and activates coagulation factors V, VIII (F8; <a href="/entry/300841">300841</a>), and XIII (F13A1; <a href="/entry/134570">134570</a>). Thrombin also inhibits coagulation by activating protein C (PROC; <a href="/entry/612283">612283</a>) (summary by <a href="#31" class="mim-tip-reference" title="Lancellotti, S., De Cristofaro, R. <strong>Congenital prothrombin deficiency.</strong> Semin. Thromb. Hemost. 35: 367-381, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19598065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19598065</a>] [<a href="https://doi.org/10.1055/s-0029-1225759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19598065">Lancellotti and De Cristofaro, 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19598065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#14" class="mim-tip-reference" title="Degen, S. J. F., Davie, E. W. <strong>Nucleotide sequence of the gene for human prothrombin.</strong> Biochemistry 26: 6165-6177, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2825773/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2825773</a>] [<a href="https://doi.org/10.1021/bi00393a033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2825773">Degen and Davie (1987)</a> determined the nucleotide sequence of the human prothrombin gene, which encodes a 622-residue pre-propeptide with a molecular mass of about 70 kD. The mature circulating protein has 579 residues. The prothrombin protein contains 5 domains: the propeptide (residues -43 to -1), the Gla domain (residues 1 to 40), a kringle domain (residues 41 to 155), a kringle-2 domain (residues 156 to 271), and a serine protease domain (residues 272 to 579). The prothrombin protein undergoes several cleavage events to generate the active enzyme alpha-thrombin, which is composed of a light (alpha) and heavy (beta) chain covalently linked by a disulfide bond (summary by <a href="#31" class="mim-tip-reference" title="Lancellotti, S., De Cristofaro, R. <strong>Congenital prothrombin deficiency.</strong> Semin. Thromb. Hemost. 35: 367-381, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19598065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19598065</a>] [<a href="https://doi.org/10.1055/s-0029-1225759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19598065">Lancellotti and De Cristofaro, 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2825773+19598065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Degen, S. J. F., Schaefer, L. A., Jamison, C. S., Grant, S. G., Fitzgibbon, J. J., Pai, J.-A., Chapman, V. M., Elliott, R. W. <strong>Characterization of the cDNA coding for mouse prothrombin and localization of the gene on mouse chromosome 2.</strong> DNA Cell Biol. 9: 487-498, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2222810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2222810</a>] [<a href="https://doi.org/10.1089/dna.1990.9.487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2222810">Degen et al. (1990)</a> cloned cDNAs for mouse coagulation factor II and compared the gene and predicted protein structure with that of human prothrombin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2222810" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#14" class="mim-tip-reference" title="Degen, S. J. F., Davie, E. W. <strong>Nucleotide sequence of the gene for human prothrombin.</strong> Biochemistry 26: 6165-6177, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2825773/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2825773</a>] [<a href="https://doi.org/10.1021/bi00393a033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2825773">Degen and Davie (1987)</a> determined that the prothrombin gene contains 14 exons and spans about 21 kb. The gene contains 30 Alu repeats and 2 Kpn repeats, which constitute about 40% of the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2825773" 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>Mapping</strong>
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<p><a href="#57" class="mim-tip-reference" title="Royle, N. J., Irwin, D. M., Koschinsky, M. L., MacGillivray, R. T. A., Hamerton, J. L. <strong>Human genes encoding prothrombin and ceruloplasmin map to 11p11-q12 and 3q21-24, respectively.</strong> Somat. Cell Molec. Genet. 13: 285-292, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3474786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3474786</a>] [<a href="https://doi.org/10.1007/BF01535211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3474786">Royle et al. (1987)</a> assigned the gene for human prothrombin (F2) to chromosome 11p11-q12 by analysis of a panel of somatic cell hybrid DNAs and by in situ hybridization, using both cDNA and genomic probes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3474786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Degen, S. J. F., Schaefer, L. A., Jamison, C. S., Grant, S. G., Fitzgibbon, J. J., Pai, J.-A., Chapman, V. M., Elliott, R. W. <strong>Characterization of the cDNA coding for mouse prothrombin and localization of the gene on mouse chromosome 2.</strong> DNA Cell Biol. 9: 487-498, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2222810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2222810</a>] [<a href="https://doi.org/10.1089/dna.1990.9.487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2222810">Degen et al. (1990)</a> mapped the mouse F2 gene to chromosome 2, about 1.8 map units proximal to the catalase locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2222810" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#9" class="mim-tip-reference" title="Celikel, R., McClintock, R. A., Roberts, J. R., Mendolicchio, G. L., Ware, J., Varughese, K. I., Ruggeri, Z. M. <strong>Modulation of alpha-thrombin function by distinct interactions with platelet glycoprotein Ib-alpha.</strong> Science 301: 218-221, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12855810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12855810</a>] [<a href="https://doi.org/10.1126/science.1084183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12855810">Celikel et al. (2003)</a> determined that the structure of platelet GP1BA (<a href="/entry/606672">606672</a>) bound to thrombin at 2.3-angstrom resolution and defined 2 sites that bind to exosite II and exosite I of 2 distinct alpha-thrombin molecules, respectively. GP1BA occupancy may be sequential, as the site binding to alpha-thrombin exosite I appears to be cryptic in the unoccupied receptor but exposed when a first thrombin molecule is bound through exosite II. <a href="#9" class="mim-tip-reference" title="Celikel, R., McClintock, R. A., Roberts, J. R., Mendolicchio, G. L., Ware, J., Varughese, K. I., Ruggeri, Z. M. <strong>Modulation of alpha-thrombin function by distinct interactions with platelet glycoprotein Ib-alpha.</strong> Science 301: 218-221, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12855810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12855810</a>] [<a href="https://doi.org/10.1126/science.1084183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12855810">Celikel et al. (2003)</a> suggested that these interactions may modulate alpha-thrombin function by mediating GP1BA clustering and cleavage of protease-activator receptors, which promote platelet activation, while limiting fibrinogen clotting through blockade of exosite I. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12855810" 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="Dumas, J. J., Kumar, R., Seehra, J., Somers, W. S., Mosyak, L. <strong>Crystal structure of the Gp1b-alpha-thrombin complex essential for platelet aggregation.</strong> Science 301: 222-226, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12855811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12855811</a>] [<a href="https://doi.org/10.1126/science.1083917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12855811">Dumas et al. (2003)</a> independently determined the crystal structure of the GP1BA-thrombin complex at 2.6-angstrom resolution. They found that in the crystal lattice, the periodic arrangement of GP1BA-thrombin complexes mirrors a scaffold that could serve as a driving force for tight platelet adhesion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12855811" 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="#29" class="mim-tip-reference" title="Kroh, H. K., Panizzi, P., Bock, P. E. <strong>Von Willebrand factor-binding protein is a hysteretic conformational activator of prothrombin.</strong> Proc. Nat. Acad. Sci. 106: 7786-7791, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19416890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19416890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19416890[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0811750106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19416890">Kroh et al. (2009)</a> found that von Willebrand factor-binding protein (VWFBP), which is secreted by Staphylococcus aureus, is a potent nonenzymatic conformational activator of prothrombin. VWFBP was found to share homology with staphylocoagulase, another protein secreted by Staphylococcus aureus that can activate prothrombin. However, the mechanism of VWFBP activation of prothrombin was different from that of staphylocoagulase, with VWFBP showing weaker affinity for prothrombin and resulting in a slow conformational change with a specific need for binding of the substrate fibrinogen to complete the process. The findings suggested a unique mechanism for fibrin deposition during S. aureus endocarditis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19416890" 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>Data on gene frequencies of allelic variants were tabulated by <a href="#56" class="mim-tip-reference" title="Roychoudhury, A. K., Nei, M. <strong>Human Polymorphic Genes: World Distribution.</strong> New York: Oxford Univ. Press (pub.) 1988."None>Roychoudhury and Nei (1988)</a>.</p><p><strong><em>Congenital Prothrombin Deficiency and Dysprothrombinemia</em></strong></p><p>
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Congenital prothrombin deficiency, also known as hypoprothrombinemia (<a href="/entry/613679">613679</a>), is a rare autosomal recessive disorder characterized by severe bleeding manifestations and decreased prothrombin antigen levels and activity to below 10% of normal values. Dysprothrombinemia, which is characterized by normal antigen levels but a dysfunctional prothrombin molecule, shows a more variable level in bleeding tendency, and there is often a good correlation between the levels of prothrombin activity and clinical severity. <a href="#1" class="mim-tip-reference" title="Akhavan, S., De Cristofaro, R., Peyvandi, F, Lavoretano, S., Landolfi, R., Mannucci, P. M. <strong>Molecular and functional characterization of a natural homozygous arg67-to-his mutation in the prothrombin gene of a patient with a severe procoagulant defect contrasting with a mild hemorrhagic phenotype.</strong> Blood 100: 1347-1353, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12149217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12149217</a>] [<a href="https://doi.org/10.1182/blood-2002-01-0243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12149217">Akhavan et al. (2002)</a> stated that 32 molecular defects in prothrombin had been identified. Complete prothrombin deficiency, or aprothombinemia, is believed to be incompatible with life (review by <a href="#35" class="mim-tip-reference" title="Meeks, S. L., Abshire, T. C. <strong>Abnormalities of prothrombin: a review of the pathophysiology, diagnosis, and treatment.</strong> Haemophilia 14: 1159-1163, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19141155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19141155</a>] [<a href="https://doi.org/10.1111/j.1365-2516.2008.01832.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19141155">Meeks and Abshire, 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19141155+12149217" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The allelic variants causing dysprothrombinemia are usually indicated according to the city or area where they were described for the first time: see, e.g., prothrombin Barcelona (<a href="#0002">176930.0002</a>) and prothrombin Tokushima (<a href="#0003">176930.0003</a>). The abnormalities are usually caused by a defect in activation of the protease, such as prothrombin Barcelona, or a defect in the protease itself, such as prothrombin Quick (<a href="#0004">176930.0004</a>; <a href="#0005">176930.0005</a>) and prothrombin Tokushima (reviews by <a href="#21" class="mim-tip-reference" title="Girolami, A., Scarano, L., Saggiorato, G., Girolami, B., Bertomoro, A., Marchiori, A. <strong>Congenital deficiencies and abnormalities of prothrombin.</strong> Blood Coagul. Fibrinolysis 9: 557-569, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9863703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9863703</a>] [<a href="https://doi.org/10.1097/00001721-199810000-00001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9863703">Girolami et al., 1998</a> and <a href="#31" class="mim-tip-reference" title="Lancellotti, S., De Cristofaro, R. <strong>Congenital prothrombin deficiency.</strong> Semin. Thromb. Hemost. 35: 367-381, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19598065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19598065</a>] [<a href="https://doi.org/10.1055/s-0029-1225759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19598065">Lancellotti and De Cristofaro, 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19598065+9863703" 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>Thrombophilia</em></strong></p><p>
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<a href="#46" class="mim-tip-reference" title="Poort, S. R., Rosendaal, F. R., Reitsma, P. H., Bertina, R. M. <strong>A common genetic variation in the 3-prime-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.</strong> Blood 88: 3698-3703, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8916933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8916933</a>]" pmid="8916933">Poort et al. (1996)</a> described a common genetic variation in the 3-prime untranslated region of the prothrombin gene that is associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis (THPH1; <a href="/entry/188050">188050</a>): a 20210G-A transition (<a href="#0009">176930.0009</a>). They found this single base substitution in 18% of probands of thrombophilic families, 6% of unselected consecutive patients with deep vein thrombosis, and 2% of healthy controls. <a href="#54" class="mim-tip-reference" title="Rosendaal, F. R., Siscovick, D. S., Schwartz, S. M., Psaty, B. M., Raghunathan, T. E., Vos, H. L. <strong>A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women.</strong> Blood 90: 1747-1750, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9292507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9292507</a>]" pmid="9292507">Rosendaal et al. (1997)</a> found that the mutation was associated with a 4-fold increased risk of myocardial infarction in women, while among men the risk was increased 1.5-fold (<a href="#17" class="mim-tip-reference" title="Doggen, C. J. M., Cats, V. M., Bertina, R. M., Rosendaal, F. R. <strong>Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A.</strong> Circulation 97: 1037-1041, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9531249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9531249</a>] [<a href="https://doi.org/10.1161/01.cir.97.11.1037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9531249">Doggen et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8916933+9531249+9292507" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Martinelli, I., Sacchi, E., Landi, G., Taioli, E., Duca, F., Mannucci, P. M. <strong>High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives.</strong> New Eng. J. Med. 338: 1793-1797, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9632445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9632445</a>] [<a href="https://doi.org/10.1056/NEJM199806183382502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9632445">Martinelli et al. (1998)</a> found that the 20210G-A mutation in the prothrombin gene (<a href="#0009">176930.0009</a>) and the factor V Leiden mutation (<a href="/entry/612309#0001">612309.0001</a>) are associated with 'idiopathic' cerebral vein thrombosis. The use of oral contraceptives was also strongly and independently associated with the disorder. The presence of both the prothrombin gene mutation and oral contraceptive use raised the risk of cerebral vein thrombosis further. The F2 and F5 mutations had previously been known to be common genetic determinants of deep vein thrombosis of the lower extremities. Cerebral vein thrombosis is a frightening event because of the severity of the clinical manifestations and the high mortality rate, estimated to be 5 to 30%. Clinically, cerebral vein thrombosis presents with a wide range of symptoms, including headache, focal deficits (motor or sensory), dysphasia, seizures, and impaired consciousness. The findings of <a href="#34" class="mim-tip-reference" title="Martinelli, I., Sacchi, E., Landi, G., Taioli, E., Duca, F., Mannucci, P. M. <strong>High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives.</strong> New Eng. J. Med. 338: 1793-1797, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9632445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9632445</a>] [<a href="https://doi.org/10.1056/NEJM199806183382502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9632445">Martinelli et al. (1998)</a> represent a prime example of the interaction of endogenous (genetic) and exogenous factors in causation of disease (<a href="#4" class="mim-tip-reference" title="Bertina, R. M., Rosendaal, F. R. <strong>Venous thrombosis - the interaction of genes and environment. (Letter)</strong> New Eng. J. Med. 338: 1840-1841, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9632453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9632453</a>] [<a href="https://doi.org/10.1056/NEJM199806183382510" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9632453">Bertina and Rosendaal, 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9632453+9632445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="De Stefano, V., Martinelli, I., Mannucci, P. M., Paciaroni, K., Chiusolo, P., Casorelli, I., Rossi, E., Leone, G. <strong>The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation.</strong> New Eng. J. Med. 341: 801-806, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10477778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10477778</a>] [<a href="https://doi.org/10.1056/NEJM199909093411104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10477778">De Stefano et al. (1999)</a> examined the relative risk of recurrent deep venous thrombosis using a proportional-hazards model. The authors found that while patients who were heterozygous for factor V Leiden had a risk of recurrent deep venous thrombosis that was similar to that among patients who had no known mutations in either factor II or factor V, patients who were heterozygous for both factor V Leiden and prothrombin 20210G-A had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10477778" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The factor V Leiden mutation (<a href="/entry/612309#0001">612309.0001</a>) and the 20210G-A mutation in the prothrombin gene (<a href="#0009">176930.0009</a>) are the most frequent abnormalities associated with venous thromboembolism. <a href="#33" class="mim-tip-reference" title="Martinelli, I., Bucciarelli, P., Margaglione, M., De Stefano, V., Castaman, G., Mannucci, P. M. <strong>The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both.</strong> Brit. J. Haemat. 111: 1223-1229, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11167765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11167765</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2000.02502.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11167765">Martinelli et al. (2000)</a> compared the prevalence and incidence rate of venous thromboembolism in relatives with either of these 2 mutations or both. The study population included 1,076 relatives of probands with the prothrombin gene mutation, factor V Leiden, or both, who underwent screening for inherited thrombophilia and were found to be carriers of single mutations or double mutations or who were noncarriers. The prevalence of venous thromboembolism was 5.7% in relatives with the prothrombin gene mutation, 7.8% in those with factor V Leiden, 17.1% in those with both mutations, and 2.5% in noncarriers. Annual incidences of thrombosis were 0.13%, 0.19%, 0.42%, and 0.066%, respectively. The relative risk of thrombosis was 2 times higher in carriers of the prothrombin gene mutation, 3 times higher in those with factor V Leiden, and 6 times higher in double carriers than in noncarriers. The incidence of venous thromboembolism in carriers of the prothrombin gene mutation was slightly lower than that observed in carriers of factor V Leiden, whereas in carriers of both mutations it was 2 or 3 times higher. From these findings, <a href="#33" class="mim-tip-reference" title="Martinelli, I., Bucciarelli, P., Margaglione, M., De Stefano, V., Castaman, G., Mannucci, P. M. <strong>The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both.</strong> Brit. J. Haemat. 111: 1223-1229, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11167765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11167765</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2000.02502.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11167765">Martinelli et al. (2000)</a> concluded that lifelong primary anticoagulant prophylaxis of venous thromboembolism is not needed in asymptomatic carriers of single or double mutations. Anticoagulant prophylaxis seems to be indicated only when transient risk factors for thrombosis coexist with mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11167765" 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 affected members of a Japanese family with recurrent thrombophilia, <a href="#39" class="mim-tip-reference" title="Miyawaki, Y., Suzuki, A., Fujita, J., Maki, A., Okuyama, E., Murata, M., Takagi, A., Murate, T., Kunishima, S., Sakai, M., Okamoto, K., Matsushita, T., Naoe, T., Saito, H., Kojima, T. <strong>Thrombosis from a prothrombin mutation conveying antithrombin resistance.</strong> New Eng. J. Med. 366: 2390-2396, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22716977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22716977</a>] [<a href="https://doi.org/10.1056/NEJMoa1201994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22716977">Miyawaki et al. (2012)</a> identified a heterozygous mutation in the F2 gene (R596L; <a href="#0015">176930.0015</a>). The family had originally been reported by <a href="#58" class="mim-tip-reference" title="Sakai, M., Urano, H., Iinuma, A., Okamoto, K., Ohsato, K., Shirahata, A. <strong>A family with multiple thrombosis including infancy occurrence.</strong> J. UOEH 23: 297-305, 2001. Note: Article in Japanese.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11570053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11570053</a>] [<a href="https://doi.org/10.7888/juoeh.23.297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11570053">Sakai et al. (2001)</a>. In vitro ELISA studies showed that the mutant prothrombin did not form a complex with antithrombin (SERPINC1; <a href="/entry/107300">107300</a>) even when heparin was added. A thrombin generation assay showed that the mutant prothrombin activity was lower than wildtype, but its inactivation in reconstituted plasma was exceedingly slow. <a href="#39" class="mim-tip-reference" title="Miyawaki, Y., Suzuki, A., Fujita, J., Maki, A., Okuyama, E., Murata, M., Takagi, A., Murate, T., Kunishima, S., Sakai, M., Okamoto, K., Matsushita, T., Naoe, T., Saito, H., Kojima, T. <strong>Thrombosis from a prothrombin mutation conveying antithrombin resistance.</strong> New Eng. J. Med. 366: 2390-2396, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22716977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22716977</a>] [<a href="https://doi.org/10.1056/NEJMoa1201994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22716977">Miyawaki et al. (2012)</a> concluded that although the procoagulant activity of the R596L mutant prothrombin was somewhat impaired, the antithrombin:thrombin complex was considerably impaired, causing continued facilitation of coagulation. The findings indicated that R596L was a gain-of-function mutation resulting in the resistance to antithrombin, and conferring susceptibility to thrombosis. The mutant variant was termed 'prothrombin Yukuhashi.' <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22716977+11570053" 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 Recurrent Pregnancy Loss</em></strong></p><p>
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<a href="#44" class="mim-tip-reference" title="Pihusch, R., Buchholz, T., Lohse, P., Rubsamen, H., Rogenhofer, N., Hasbargen, U., Hiller, E., Thaler, C. J. <strong>Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester.</strong> Am. J. Reprod. Immun. 46: 124-131, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11506076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11506076</a>] [<a href="https://doi.org/10.1111/j.8755-8920.2001.460202.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11506076">Pihusch et al. (2001)</a> studied clotting factors in 102 patients with 2 or more consecutive spontaneous abortions (RPRGL2; <a href="/entry/614390">614390</a>) compared to 128 women without miscarriage and found that heterozygosity for the 20210G-A mutation of prothrombin (<a href="#0009">176930.0009</a>) was more common in patients with abortions in the first trimester (p = 0.027; odds ratio, 8.5). Noting that in addition to fibrin generation, thrombin also activates tissue components represented in the placenta and induces cellular responses, <a href="#44" class="mim-tip-reference" title="Pihusch, R., Buchholz, T., Lohse, P., Rubsamen, H., Rogenhofer, N., Hasbargen, U., Hiller, E., Thaler, C. J. <strong>Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester.</strong> Am. J. Reprod. Immun. 46: 124-131, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11506076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11506076</a>] [<a href="https://doi.org/10.1111/j.8755-8920.2001.460202.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11506076">Pihusch et al. (2001)</a> suggested that increased prothrombin levels might affect placental function by influencing pivotal mechanisms such as cell adhesion, smooth muscle proliferation, and vasculogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11506076" 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>Several observations suggest that prothrombin may serve a broader physiologic role than simply stemming blood loss, including the identification of multiple G protein-coupled, thrombin-activated receptors, and the well-documented mitogenic activity of thrombin in in vitro test systems. To explore further the physiologic roles of prothrombin in vivo, <a href="#63" class="mim-tip-reference" title="Sun, W. Y., Witte, D. P., Degen, J. L., Colbert, M. C., Burkart, M. C., Holmback, K., Xiao, Q., Bugge, T. H., Degen, S. J. F. <strong>Prothrombin deficiency results in embryonic and neonatal lethality in mice.</strong> Proc. Nat. Acad. Sci. 95: 7597-7602, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9636195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9636195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9636195[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.13.7597" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9636195">Sun et al. (1998)</a> generated prothrombin-deficient mice by knockout techniques. Inactivation of the F2 gene led to partial embryonic lethality with more than half of the F2 -/- embryos dying between embryonic days 9.5 and 11.5. Bleeding into the yolk sac cavity and varying degrees of tissue necrosis were observed in many of the F2 -/- embryos within this gestational time frame. At least one-quarter of the F2 -/- mice survived to term, but they ultimately developed fatal hemorrhagic events and died within a few days of birth. The study demonstrated that F2 is important in maintaining vascular integrity during development as well as in postnatal life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9636195" 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> rs62623459 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs62623459;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/rs62623459?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=rs62623459" 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=rs62623459" 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=RCV000014229 OR RCV000994617 OR RCV001108917 OR RCV001108918 OR RCV001794445" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014229, RCV000994617, RCV001108917, RCV001108918, RCV001794445" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014229...</a>
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<p><a href="#6" class="mim-tip-reference" title="Board, P. G., Shaw, D. C. <strong>Determination of the amino acid substitution in human prothrombin type 3 (157 glu-to-lys) and the localization of a third thrombin cleavage site.</strong> Brit. J. Haemat. 54: 245-254, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6405779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6405779</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1983.tb02092.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6405779">Board and Shaw (1983)</a> showed that prothrombin type 3 is due to a glu157-to-lys (E157K) substitution in the F2 gene. This was the first identification of the specific change in a variant prothrombin, isolated from individuals heterozygous for prothrombin type 3. This substitution explained the relatively slow electrophoretic mobility of prothrombin type 3 compared to wildtype at alkaline pH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6405779" 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> rs121918477 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918477;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/rs121918477?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=rs121918477" 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=rs121918477" 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=RCV002468924" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002468924" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002468924</a>
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<p>This F2 variant is referred to as prothrombin Barcelona.</p><p>In a patient with normal prothrombin antigen levels, but low prothrombin coagulant activity (see <a href="/entry/613679">613679</a>) (<a href="#50" class="mim-tip-reference" title="Rabiet, M.-J., Elion, J., Benarous, R., Labie, D., Josso, F. <strong>Activation of prothrombin Barcelona: evidence for active high molecular weight intermediates.</strong> Biochim. Biophys. Acta 584: 66-75, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/444582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">444582</a>] [<a href="https://doi.org/10.1016/0304-4165(79)90236-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="444582">Rabiet et al., 1979</a>), <a href="#51" class="mim-tip-reference" title="Rabiet, M.-J., Furie, B. C., Furie, B. <strong>Molecular defect of prothrombin Barcelona: substitution of cysteine for arginine at residue 273.</strong> J. Biol. Chem. 261: 15045-15048, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3771562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3771562</a>]" pmid="3771562">Rabiet et al. (1986)</a> found that the defect was due to an arg271-to-cys (R271C) substitution in the F2 gene. The peptide bond between arg271 and thr272 is one of 2 sites of cleavage by factor Xa, indicating that activation of the variant Barcelona prothrombin protein to functional thrombin was impaired. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=444582+3771562" 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> rs121918478 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918478;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/rs121918478?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=rs121918478" 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=rs121918478" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>This F2 variant is referred to as prothrombin Tokushima.</p><p>In a 10-year-old Japanese girl who was compound heterozygous for dysprothrombinemia (see <a href="/entry/613679">613679</a>) and hypoprothrombinemia, <a href="#38" class="mim-tip-reference" title="Miyata, T., Morita, T., Inomoto, T., Kawauchi, S., Shirakami, A., Iwanaga, S. <strong>Prothrombin Tokushima, a replacement of arginine-418 by tryptophan that impairs the fibrinogen clotting activity of derived thrombin Tokushima.</strong> Biochemistry 26: 1117-1122, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3567158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3567158</a>] [<a href="https://doi.org/10.1021/bi00378a020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3567158">Miyata et al. (1987)</a> identified a heterozygous 9490T-to-C transition in the F2 gene, resulting in an arg418-to-trp (R418W) substitution on the maternal allele. The patient had originally been reported by <a href="#26" class="mim-tip-reference" title="Inomoto, T., Shirakami, A., Kawauchi, S., Shigekiyo, T., Saito, S., Miyoshi, K., Morita, T., Iwanaga, S. <strong>Prothrombin Tokushima: characterization of dysfunctional thrombin derived from a variant of human prothrombin.</strong> Blood 69: 565-569, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3801671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3801671</a>]" pmid="3801671">Inomoto et al. (1987)</a>, who determined that the prothrombin variant showed about 22% clotting activity and reduced platelet aggregating activity, suggesting a defect in the catalytic region (<a href="#31" class="mim-tip-reference" title="Lancellotti, S., De Cristofaro, R. <strong>Congenital prothrombin deficiency.</strong> Semin. Thromb. Hemost. 35: 367-381, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19598065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19598065</a>] [<a href="https://doi.org/10.1055/s-0029-1225759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19598065">Lancellotti and De Cristofaro, 2009</a>). <a href="#60" class="mim-tip-reference" title="Shirakami, A., Kawauchi, S., Shigekiyo, T., Ono, H., Kataoka, K., Miyoshi, K., Yura, Y. <strong>Prothrombin Tokushima: a family with heterozygosity for dysprothrombin and hypoprothrombin. (Abstract)</strong> Acta Haemat. Jpn. 46: 589 only, 1983."None>Shirakami et al. (1983)</a> and <a href="#61" class="mim-tip-reference" title="Shirakami, A., Kawauchi, S. <strong>Congenital dysprothrombinemia.</strong> Acta Haemat. Jpn. 47: 1697-1704, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6085205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6085205</a>]" pmid="6085205">Shirakami and Kawauchi (1984)</a> concluded from study of this pedigree that the proband was a 'double heterozygote' for a dysprothrombinemia variant (R418W), inherited from the mother, and a hypoprothrombinemia (<a href="/entry/613679">613679</a>) variant, inherited from the father. Indeed, <a href="#27" class="mim-tip-reference" title="Iwahana, H., Yoshimoto, K., Shigekiyo, T., Shirakami, A., Saito, S., Itakura, M. <strong>Detection of a single base substitution of the gene for prothrombin Tokushima: the application of PCR-SSCP for the genetic and molecular analysis of dysprothrombinemia.</strong> Int. J. Hemat. 55: 93-100, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1349838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1349838</a>]" pmid="1349838">Iwahana et al. (1992)</a> determined that the hypoprothombinemia variant inherited from the father was a 1-bp insertion (4177insT; <a href="#0008">176930.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6085205+3567158+19598065+1349838+3801671" 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">rs121918479 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918479;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=rs121918479" 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=rs121918479" 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=RCV002468926" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002468926" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002468926</a>
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<p>This F2 variant is referred to as prothrombin Quick I.</p><p>A patient with dysprothrombinemia (see <a href="/entry/613679">613679</a>) originally studied by <a href="#49" class="mim-tip-reference" title="Quick, A. J., Pisciotta, A. V., Hussey, C. V. <strong>Congenital hypoprothrombinemic states.</strong> Arch. Intern. Med. 95: 2-14, 1955."None>Quick et al. (1955)</a>, <a href="#48" class="mim-tip-reference" title="Quick, A. J., Hussey, C. V. <strong>Hereditary hypoprothrombinemias.</strong> Lancet 279: 173-177, 1962. Note: Originally Volume 1.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14489469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14489469</a>] [<a href="https://doi.org/10.1016/s0140-6736(62)91073-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14489469">Quick and Hussey (1962)</a>, and <a href="#43" class="mim-tip-reference" title="Owen, C. A., Jr., Henriksen, R. A., McDuffie, F. C., Mann, K. G. <strong>Prothrombin Quick: a newly identified dysprothrombinemia.</strong> Mayo Clin. Proc. 53: 29-33, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/625142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">625142</a>]" pmid="625142">Owen et al. (1978)</a> was later found to be compound heterozygous for 2 defective alleles in the F2 gene. <a href="#22" class="mim-tip-reference" title="Henriksen, R. A., Mann, K. G. <strong>Identification of the primary structural defect in the dysthrombin thrombin Quick I: substitution of cysteine for arginine-382.</strong> Biochemistry 27: 9160-9165, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3242619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3242619</a>] [<a href="https://doi.org/10.1021/bi00426a013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3242619">Henriksen and Mann (1988)</a> identified a heterozygous C-to-T transition resulting in an arg382-to-cys (R382C) substitution, and <a href="#23" class="mim-tip-reference" title="Henriksen, R. A., Mann, K. G. <strong>Substitution of valine for glycine-558 in the congenital dysthrombin thrombin Quick II alters primary substrate specificity.</strong> Biochemistry 28: 2078-2082, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2719946/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2719946</a>] [<a href="https://doi.org/10.1021/bi00431a017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2719946">Henriksen and Mann (1989)</a> identified a heterozygous G-to-T transversion resulting in a gly558-to-val (G558V; <a href="#0005">176930.0005</a>) substitution. The patient had less than 2% of normal prothrombin activity. Laboratory studies by Henriksen and Mann (<a href="#22" class="mim-tip-reference" title="Henriksen, R. A., Mann, K. G. <strong>Identification of the primary structural defect in the dysthrombin thrombin Quick I: substitution of cysteine for arginine-382.</strong> Biochemistry 27: 9160-9165, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3242619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3242619</a>] [<a href="https://doi.org/10.1021/bi00426a013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3242619">1988</a>, <a href="#23" class="mim-tip-reference" title="Henriksen, R. A., Mann, K. G. <strong>Substitution of valine for glycine-558 in the congenital dysthrombin thrombin Quick II alters primary substrate specificity.</strong> Biochemistry 28: 2078-2082, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2719946/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2719946</a>] [<a href="https://doi.org/10.1021/bi00431a017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2719946">1989</a>) showed that both variants resulted in a structural change in the catalytic region causing defective interaction with fibrinogen. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=625142+14489469+2719946+3242619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Banfield, D. K., MacGillivray, R. T. A. <strong>Partial characterization of vertebrate prothrombin cDNAs: amplification and sequence analysis of the B chain of thrombin from nine different species.</strong> Proc. Nat. Acad. Sci. 89: 2779-2783, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1557383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1557383</a>] [<a href="https://doi.org/10.1073/pnas.89.7.2779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1557383">Banfield and MacGillivray (1992)</a> found that the arginine residue at codon 382 is conserved in 11 species ranging from the human to the gecko (a lizard), the newt, and fish, including rainbow trout, sturgeon, and the hagfish. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1557383" 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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F2, GLY558VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918480 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918480;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=rs121918480" 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=rs121918480" 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=RCV002468927" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002468927" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002468927</a>
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<p>This F2 variant is referred to as prothrombin Quick II.</p><p>See <a href="#0004">176930.0004</a> and <a href="#23" class="mim-tip-reference" title="Henriksen, R. A., Mann, K. G. <strong>Substitution of valine for glycine-558 in the congenital dysthrombin thrombin Quick II alters primary substrate specificity.</strong> Biochemistry 28: 2078-2082, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2719946/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2719946</a>] [<a href="https://doi.org/10.1021/bi00431a017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2719946">Henriksen and Mann (1989)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2719946" 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">rs121918481 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918481;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=rs121918481" 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=rs121918481" 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=RCV002468928" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002468928" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002468928</a>
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<p>This F2 variant is referred to as prothrombin Himi I.</p><p>In a girl with dysprothrombinemia (see <a href="/entry/613679">613679</a>), <a href="#41" class="mim-tip-reference" title="Morishita, E., Saito, M., Kumabashiri, I., Asakura, H., Matsuda, T., Yamaguchi, K. <strong>Prothrombin Himi: a compound heterozygote for two dysfunctional prothrombin molecules (met-337-to-thr and arg-388-to-his).</strong> Blood 80: 2275-2280, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1421398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1421398</a>]" pmid="1421398">Morishita et al. (1992)</a> found a congenitally dysfunctional form of prothrombin, called prothrombin Himi, which was associated with reduced fibrinogen clotting activity, although it retained full hydrolytic activity toward synthetic substrates. Because previous findings suggested that the functional defect of prothrombin Himi was caused by an abnormality in the thrombin portion of the protein, <a href="#41" class="mim-tip-reference" title="Morishita, E., Saito, M., Kumabashiri, I., Asakura, H., Matsuda, T., Yamaguchi, K. <strong>Prothrombin Himi: a compound heterozygote for two dysfunctional prothrombin molecules (met-337-to-thr and arg-388-to-his).</strong> Blood 80: 2275-2280, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1421398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1421398</a>]" pmid="1421398">Morishita et al. (1992)</a> amplified the genomic DNA regions corresponding to exons 8 through 14 and applied single-strand conformation polymorphism analysis. Two variant conformers in exon 10 were identified in the proband with this variant: an 8751T-C transition resulting in a met337-to-thr (M337T) substitution inherited from the father, and an 8904G-A transition resulting in an arg388-to-his (R388H; <a href="#0007">176930.0007</a>) substitution inherited from the mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1421398" 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> rs121918482 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918482;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/rs121918482?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=rs121918482" 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=rs121918482" 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=RCV000014235" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014235" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014235</a>
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<p>This F2 variant is referred to as prothrombin Himi II.</p><p>See <a href="#0006">176930.0006</a> and <a href="#41" class="mim-tip-reference" title="Morishita, E., Saito, M., Kumabashiri, I., Asakura, H., Matsuda, T., Yamaguchi, K. <strong>Prothrombin Himi: a compound heterozygote for two dysfunctional prothrombin molecules (met-337-to-thr and arg-388-to-his).</strong> Blood 80: 2275-2280, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1421398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1421398</a>]" pmid="1421398">Morishita et al. (1992)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1421398" 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>.0008 HYPOPROTHROMBINEMIA</strong>
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F2, 1-BP INS, 4177T
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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> rs387906522 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906522;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/rs387906522?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=rs387906522" 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=rs387906522" 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=RCV000014236" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014236" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014236</a>
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<p>In a Japanese girl who was compound heterozygous for hypoprothrombinemia (<a href="/entry/613679">613679</a>) and dysprothrombinemia, <a href="#27" class="mim-tip-reference" title="Iwahana, H., Yoshimoto, K., Shigekiyo, T., Shirakami, A., Saito, S., Itakura, M. <strong>Detection of a single base substitution of the gene for prothrombin Tokushima: the application of PCR-SSCP for the genetic and molecular analysis of dysprothrombinemia.</strong> Int. J. Hemat. 55: 93-100, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1349838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1349838</a>]" pmid="1349838">Iwahana et al. (1992)</a> demonstrated a heterozygous 1-bp insertion (4177insT) in exon 6 of the F2 gene inherited from her father. This defect was the basis of the hypoprothrombinemia. The resulting frameshift mutation caused both an altered amino acid sequence from codon 114 and a premature termination codon (TGA) at codon 174 in exon 7. Because exon 7 encodes the kringle-2 domain preceding the thrombin sequence, the frameshift led to the null prothrombin phenotype. The girl was compound heterozygous for 4177insT and an R418W (<a href="#0003">176930.0003</a>) substitution, which was the basis of the dysprothrombinemia (see <a href="/entry/613679">613679</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1349838" 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 THROMBIN DEFECT</strong>
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STROKE, ISCHEMIC, SUSCEPTIBILITY TO, INCLUDED<br />
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PREGNANCY LOSS, RECURRENT, SUSCEPTIBILITY TO, 2, INCLUDED
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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> rs1799963 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1799963;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/rs1799963?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=rs1799963" 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=rs1799963" 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=RCV000014237 OR RCV000014238 OR RCV000022729 OR RCV000205022 OR RCV000826090 OR RCV001091960 OR RCV001794446 OR RCV002468555 OR RCV005042047" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014237, RCV000014238, RCV000022729, RCV000205022, RCV000826090, RCV001091960, RCV001794446, RCV002468555, RCV005042047" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014237...</a>
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<p><a href="#53" class="mim-tip-reference" title="Rosendaal, F. R., Doggen, C. J. M., Zivelin, A., Arruda, V. R., Aiach, M., Siscovick, D. S., Hillarp, A., Watzke, H. H., Bernardi, F., Cumming, A. M., Preston, F. E., Reitsma, P. H. <strong>Geographic distribution of the 20210 G to A prothrombin variant.</strong> Thromb. Haemost. 79: 706-708, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9569177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9569177</a>]" pmid="9569177">Rosendaal et al. (1998)</a> presented data from 11 centers and 9 countries, representing a total of 5,527 tested individuals. Among these, 111 heterozygous carriers of the 20210A mutation were found, yielding an overall prevalence of 2.0%. In southern Europe, the prevalence was 3.0%, nearly twice as high as the prevalence in northern Europe (1.7%). The prothrombin variant appeared to be rare in individuals of Asian and African descent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9569177" 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 discern whether the 20210G-A polymorphism originated from a single or recurrent mutation event, <a href="#66" class="mim-tip-reference" title="Zivelin, A., Rosenberg, N., Faier, S., Kornbrot, N., Peretz, H., Mannhalter, C., Horellou, M. H., Seligsohn, U. <strong>A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene.</strong> Blood 92: 1119-1124, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9694698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9694698</a>]" pmid="9694698">Zivelin et al. (1998)</a> determined allele frequencies of 4 dimorphisms spanning 16 of 21 kb of the factor II gene in 133 unrelated Caucasian subjects of Jewish, Austrian, and French origins who bore factor II 20210A (10 homozygotes and 123 heterozygotes) and 110 Caucasian controls. Remarkable differences in the allele frequencies for each dimorphism were observed between the study groups (p = 0.0007 or less), indicating strong linkage disequilibrium and suggesting a founder effect. Indeed, a founder haplotype was present in 68% of 20210A mutant alleles and in only 34% of 20210G normal alleles (p less than 0.0001). These data strongly supported a single origin for the factor II polymorphism. Because the polymorphism is rare or absent in non-Caucasian populations, it probably occurred after divergence of Africans from non-Africans and of Caucasoids from Mongoloid subpopulations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9694698" 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="#52" class="mim-tip-reference" title="Rees, D. C., Chapman, N. H., Webster, M. T., Guerreiro, J. F., Rochette, J., Clegg, J. B. <strong>Born to clot: the European burden.</strong> Brit. J. Haemat. 105: 564-566, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10233439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10233439</a>]" pmid="10233439">Rees et al. (1999)</a> analyzed samples from 22 different non-European countries and found that the prothrombin 20210G-A variant, like factor V Leiden (<a href="/entry/612309#0001">612309.0001</a>), is rare outside Europe. Of 1,811 non-Europeans tested, they found only 1 individual, in India, who had the mutation in heterozygous state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10233439" 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="#65" class="mim-tip-reference" title="Zivelin, A., Mor-Cohen, R., Kovalsky, V., Kornbrot, N., Conard, J., Peyvandi, F., Kyrle, P. A., Bertina, R., Peyvandi, F., Emmerich, J., Seligsohn, U. <strong>Prothrombin 20210G-A is an ancestral prothrombotic mutation that occurred in whites approximately 24,000 years ago.</strong> Blood 107: 4666-4668, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16493002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16493002</a>] [<a href="https://doi.org/10.1182/blood-2005-12-5158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16493002">Zivelin et al. (2006)</a> analyzed the frequencies of 5 SNPs and 9 microsatellites flanking the prothrombin gene in 88 homozygotes for 20210A and 66 homozygotes for 20210G. For estimating the age of the prothrombin 20210G-A mutation, they analyzed linkage disequilibrium between the mutation and the multiple markers that had been assessed. The analysis yielded an age estimate of 23,720 years. A similar analysis was performed for factor V Leiden (<a href="/entry/612309#0001">612309.0001</a>) yielding an age estimate of 21,340 years. The occurrence of the 2 mutations in whites toward the end of the last glaciation and their presently wide distribution in whites suggested selective evolutionary advantages for which some evidence was reported (diminished blood loss) or is controversial (protection against infections). The selected disadvantage from thrombosis is unlikely because until recent centuries humans did not live long enough to manifest a meaningful incidence of thrombosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16493002" 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>Thrombophilia</p><p><a href="#46" class="mim-tip-reference" title="Poort, S. R., Rosendaal, F. R., Reitsma, P. H., Bertina, R. M. <strong>A common genetic variation in the 3-prime-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.</strong> Blood 88: 3698-3703, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8916933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8916933</a>]" pmid="8916933">Poort et al. (1996)</a> found that a common genetic 20210G-A transition in the 3-prime untranslated region of the prothrombin gene (<a href="#14" class="mim-tip-reference" title="Degen, S. J. F., Davie, E. W. <strong>Nucleotide sequence of the gene for human prothrombin.</strong> Biochemistry 26: 6165-6177, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2825773/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2825773</a>] [<a href="https://doi.org/10.1021/bi00393a033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2825773">Degen and Davie, 1987</a>) was associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis (THPH1; <a href="/entry/188050">188050</a>). The SNP was found in 18% of probands of families with thrombosis, 6% of unselected consecutive patients with deep vein thrombosis, and 2% of healthy controls. <a href="#54" class="mim-tip-reference" title="Rosendaal, F. R., Siscovick, D. S., Schwartz, S. M., Psaty, B. M., Raghunathan, T. E., Vos, H. L. <strong>A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women.</strong> Blood 90: 1747-1750, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9292507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9292507</a>]" pmid="9292507">Rosendaal et al. (1997)</a> found that the mutation was associated with a 4-fold increased risk of myocardial infarction in women, while among men the risk was increased 1.5-fold (<a href="#17" class="mim-tip-reference" title="Doggen, C. J. M., Cats, V. M., Bertina, R. M., Rosendaal, F. R. <strong>Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A.</strong> Circulation 97: 1037-1041, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9531249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9531249</a>] [<a href="https://doi.org/10.1161/01.cir.97.11.1037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9531249">Doggen et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2825773+8916933+9531249+9292507" 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="Franco, R. F., Trip, M. D., ten Cate, H., van den Ende, A., Prins, M. H., Kastelein, J. J. P., Reitsma, P. H. <strong>The 20210G-A mutation in the 3-prime-untranslated region of the prothrombin gene and the risk for arterial thrombotic disease.</strong> Brit. J. Haemat. 104: 50-54, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10027711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10027711</a>] [<a href="https://doi.org/10.1046/j.1365-2141.1999.01149.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10027711">Franco et al. (1999)</a> found a frequency of the 20210A allele of 1% in a 400-member healthy control population and 2.7% in 263 patients with proven premature atherosclerotic disease. All heterozygotes in the patient group were found to have had a myocardial infarction. In addition, the data provided evidence for an association of the mutation with excessive thrombin generation, which may contribute to the understanding of its role in venous and arterial disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10027711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Chamouard, P., Pencreach, E., Maloisel, F., Grunebaum, L., Ardizzone, J.-F., Meyer, A., Gaub, M.-P., Goetz, J., Baumann, R., Uring-Lambert, B., Levy, S., Dufour, P., Hauptmann, G., Oudet, P. <strong>Frequent factor II G20210A mutation in idiopathic portal vein thrombosis.</strong> Gastroenterology 116: 144-148, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9869612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9869612</a>] [<a href="https://doi.org/10.1016/s0016-5085(99)70238-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9869612">Chamouard et al. (1999)</a> studied the frequency of the factor II 20210G-A mutation in 10 white European patients with idiopathic portal vein thrombosis. They studied 5 women and 5 men; mean age was 50.4 years. The frequency of the 20210G-A mutation was found to be 40% in idiopathic portal vein thrombosis compared with 4.8% in controls or patients with nonidiopathic portal vein thrombosis or deep vein thrombosis. The frequency of the factor V Leiden mutation (<a href="/entry/612309#0001">612309.0001</a>) was similar in subjects with portal vein thrombosis and in controls but was increased in patients with deep vein thrombosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9869612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="De Stefano, V., Martinelli, I., Mannucci, P. M., Paciaroni, K., Chiusolo, P., Casorelli, I., Rossi, E., Leone, G. <strong>The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation.</strong> New Eng. J. Med. 341: 801-806, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10477778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10477778</a>] [<a href="https://doi.org/10.1056/NEJM199909093411104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10477778">De Stefano et al. (1999)</a> found that patients who were heterozygous for both factor V Leiden (1691G-A; <a href="/entry/612309#0001">612309.0001</a>) and prothrombin 20210G-A had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. Patients who were heterozygous for factor V Leiden had a risk of recurrent deep venous thrombosis that was similar to that among patients who had no known mutations in either factor II or factor V. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10477778" 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 Spanish family, <a href="#11" class="mim-tip-reference" title="Corral, J., Zuazu-Jausoro, I., Rivera, J., Gonzalez-Conejero, R., Ferrer, F., Vicente, V. <strong>Clinical and analytical relevance of the combination of prothrombin 20210A/A and factor V Leiden: results from a large family.</strong> Brit. J. Haemat. 105: 560-563, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10233438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10233438</a>]" pmid="10233438">Corral et al. (1999)</a> identified 3 subjects homozygous for the 20210A prothrombin mutation who additionally were heterozygous for factor V Leiden. The combination of the 2 mutations increased the risk of developing venous thrombotic episodes at an earlier age. However, even in association with factor V Leiden, the homozygous condition of the 20210A prothrombin mutation required additional risk factors to induce a thrombotic event. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10233438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Humpert, P. M., Isermann, B., Rudofsky, G., Ziegler, R., Bierhaus, A., Ritz, E., Nawroth, P. P. <strong>The 20210 G to A prothrombin polymorphism and late complications in type 1 diabetes mellitus. (Letter)</strong> Thromb. Haemost. 81: 164 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10348712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10348712</a>]" pmid="10348712">Humpert et al. (1999)</a> screened 384 type 1 diabetic patients for the 20210G-A prothrombin polymorphism and detected the variant in 9 patients. There was no increase in the incidence of coronary heart disease, nephropathy, or retinopathy among diabetic patients carrying the 20210G-A polymorphism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10348712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Meyer, M., Kutscher, G., Vogel, G. <strong>Simultaneous genotyping for factor V Leiden and prothrombin G20210A variant by a multiplex PCR-SSCP assay on whole blood. (Letter)</strong> Thromb. Haemost. 81: 162-163, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10348711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10348711</a>]" pmid="10348711">Meyer et al. (1999)</a> described a method for simultaneously genotyping for factor V Leiden and the prothrombin 20210G-A variant by a multiplex PCR-SSCP assay on whole blood. <a href="#47" class="mim-tip-reference" title="Prohaska, W., Schmidt, M., Mannebach, H., Gleichmann, U., Kleesiek, K. <strong>The prevalence of the prothrombin 20210G-A mutation is not increased in angiographically confirmed coronary artery disease. (Letter)</strong> Thromb. Haemost. 81: 161-162, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10348710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10348710</a>]" pmid="10348710">Prohaska et al. (1999)</a> studied 284 patients with angiographically confirmed coronary artery disease for the presence of the 20210G-A polymorphism of the prothrombin gene and compared them with 340 healthy controls. The prevalence of the mutation was similar in both groups. There was a mild increase in the frequency of the mutation in a group of 294 venous thrombosis patients compared with the healthy controls (odds ratio, 2.90; 95% CI, 1.25-6.9). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10348711+10348710" 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>One of the main factors of sudden hearing impairment, vestibular disturbance (tinnitus), is generally thought to be an acute labyrinthine ischemia; the most common mechanism of sudden hearing loss appears to be impaired cochlear blood circulation. <a href="#36" class="mim-tip-reference" title="Mercier, E., Quere, I., Chabert, R., Lallemant, J.-G., Daures, J.-P., Berlan, J., Gris, J.-C. <strong>The 20210A allele of the prothrombin gene is an independent risk factor for perception deafness in patients with venous thromboembolic antecedents. (Letter)</strong> Blood 93: 3150-3152, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10336270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10336270</a>]" pmid="10336270">Mercier et al. (1999)</a> provided evidence that the 20210A allele of the prothrombin gene is a risk factor for perception deafness. Among 368 patients (median age, 41 years) with spontaneous deep vein thrombosis, 18 (12 women and 6 men, 38 to 69 years of age) had also suffered from acute unilateral hearing impairment. Six of the 18 were heterozygous for the 20210A allele. In a group of 395 nonthrombotic consecutive patients studied in the same laboratory for hemorrhagic symptoms or thrombocytopenia over the same period of time, 4 had acute unilateral perception deafness; of 395 nonthrombotic and nonhemorrhagic sex- and age-matched controls, 6 had acute unilateral perception deafness. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10336270" 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="#62" class="mim-tip-reference" title="Souto, J. C., Mateo, J., Soria, J. M., Llobet, D., Coll, I., Borrell, M., Fontcuberta, J. <strong>Homozygotes for prothrombin gene 20210 A allele in a thrombophilic family without clinical manifestations of venous thromboembolism.</strong> Haematologica 84: 627-632, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10406905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10406905</a>]" pmid="10406905">Souto et al. (1999)</a> reported a family illustrating the complexity of thrombotic disease in relation to the 20210A variant. The pedigree was ascertained through a proband with idiopathic thrombophilia. The family members who had a history of thromboembolism were heterozygous carriers of the 20210A variant. In addition, 4 relatives who were heterozygous as well as 2 who were homozygous for the 20210A allele failed to show clinical manifestations. The 2 homozygotes were 51 and 19 years old. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10406905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Gehring, N. H., Frede, U., Neu-Yilik, G., Hundsdoerfer, P., Vetter, B., Hentze, M. W., Kulozik, A. E. <strong>Increased efficiency of mRNA 3-prime end formation: a new genetic mechanism contributing to hereditary thrombophilia.</strong> Nature Genet. 28: 389-392, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11443298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11443298</a>] [<a href="https://doi.org/10.1038/ng578" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11443298">Gehring et al. (2001)</a> demonstrated that the 20210G-A mutation does not affect the amount of pre-mRNA, the site of 3-prime end cleavage, or the length of poly(A) tail of the mature mRNA. Rather, <a href="#20" class="mim-tip-reference" title="Gehring, N. H., Frede, U., Neu-Yilik, G., Hundsdoerfer, P., Vetter, B., Hentze, M. W., Kulozik, A. E. <strong>Increased efficiency of mRNA 3-prime end formation: a new genetic mechanism contributing to hereditary thrombophilia.</strong> Nature Genet. 28: 389-392, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11443298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11443298</a>] [<a href="https://doi.org/10.1038/ng578" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11443298">Gehring et al. (2001)</a> demonstrated that the physiologic F2 3-prime end cleavage signal is inefficient and that F2 20210G-A represents a gain-of-function mutation, causing increased cleavage site recognition, increased 3-prime end processing, and increased mRNA accumulation and protein synthesis. Enhanced mRNA 3-prime end formation efficiency emerges as a novel principle causing a genetic disorder and explains the role of the F2 20210G-A mutation in the pathogenesis of thrombophilia. <a href="#20" class="mim-tip-reference" title="Gehring, N. H., Frede, U., Neu-Yilik, G., Hundsdoerfer, P., Vetter, B., Hentze, M. W., Kulozik, A. E. <strong>Increased efficiency of mRNA 3-prime end formation: a new genetic mechanism contributing to hereditary thrombophilia.</strong> Nature Genet. 28: 389-392, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11443298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11443298</a>] [<a href="https://doi.org/10.1038/ng578" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11443298">Gehring et al. (2001)</a> concluded that their work illustrates the pathophysiologic importance of quantitatively minor aberrations of RNA metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11443298" 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>Although the 20210G-A mutation in heterozygous state carries an increased risk of a first venous thromboembolic episode, <a href="#13" class="mim-tip-reference" title="De Stefano, V., Martinelli, I., Mannucci, P. M., Paciaroni, K., Rossi, E., Chiusolo, P., Casorelli, I., Leone, G. <strong>The risk of recurrent venous thromboembolism among heterozygous carriers of the G20210A prothrombin gene mutation.</strong> Brit. J. Haemat. 113: 630-635, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11380448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11380448</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2001.02827.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11380448">De Stefano et al. (2001)</a> found that the risk of spontaneous recurrent venous thromboembolism was similar to that in patients with normal genotype. They concluded that carriers of the prothrombin mutation should be treated with oral anticoagulants after a first deep venous thrombosis for a similar length of time as patients with a normal genotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11380448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Laczika, K., Lang, I. M., Quehenberger, P., Mannhalter, C., Muhm, M., Klepetko, W., Kyrle, P. A. <strong>Unilateral chronic thromboembolic pulmonary disease associated with combined inherited thrombophilia.</strong> Chest 121: 286-289, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11796466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11796466</a>] [<a href="https://doi.org/10.1378/chest.121.1.286" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11796466">Laczika et al. (2002)</a> described a 19-year-old woman with the joint occurrence of type I antithrombin III deficiency (<a href="/entry/613118">613118</a>) and a heterozygous prothrombin 20210G-A mutation, who developed chronic thromboembolic pulmonary hypertension on the basis of total occlusion of the right pulmonary artery. Pulmonary vascular patency was restored successfully by surgical pulmonary thromboendarterectomy performed 24 weeks after the initial clinical presentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11796466" 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="#59" class="mim-tip-reference" title="Segal, J. B., Brotman, D. J., Necochea, A. J., Emadi, A., Samal, L., Wilson, L. M., Crim, M. T., Bass, E. B. <strong>Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review.</strong> JAMA 301: 2472-2485, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19531787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19531787</a>] [<a href="https://doi.org/10.1001/jama.2009.853" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19531787">Segal et al. (2009)</a> provided a metaanalysis of the predictive value of the prothrombin 20210G-A mutation for venous thromboembolism using a literature review of 10 relevant articles. Although heterozygosity for prothrombin 20210G-A in probands conferred a risk of 1.45, the confidence interval ranged from 0.96 to 2.2, suggesting that the mutation was not predictive of recurrent venous thromboembolism compared to those without the mutation. In addition, there was insufficient evidence regarding the predictive value of homozygosity for prothrombin 20210G-A in probands, and for the predictive value of being a mutation carrier in relatives of probands with the mutation. It remained unknown whether testing improved clinical outcomes. <a href="#59" class="mim-tip-reference" title="Segal, J. B., Brotman, D. J., Necochea, A. J., Emadi, A., Samal, L., Wilson, L. M., Crim, M. T., Bass, E. B. <strong>Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review.</strong> JAMA 301: 2472-2485, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19531787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19531787</a>] [<a href="https://doi.org/10.1001/jama.2009.853" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19531787">Segal et al. (2009)</a> concluded that there is insufficient evidence to support the hypothesis that 20210G-A confers a significantly increased risk for venous thromboembolism in terms of genetic testing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19531787" 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>Ischemic Stroke</p><p>In a comprehensive metaanalysis of 19 case-control studies including 3,028 white adult patients, <a href="#8" class="mim-tip-reference" title="Casas, J. P., Hingorani, A. D., Bautista, L. E., Sharma, P. <strong>Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18000 cases and 58000 controls.</strong> Arch. Neurol. 61: 1652-1662, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15534175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15534175</a>] [<a href="https://doi.org/10.1001/archneur.61.11.1652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15534175">Casas et al. (2004)</a> found a statistically significant association between ischemic stroke (<a href="/entry/601367">601367</a>) and the 20210G-A substitution (odds ratio of 1.44). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15534175" 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>Budd-Chiari Syndrome</p><p>In a 37-year-old Caucasian male with polycythemia vera who had developed Budd-Chiari syndrome (BDCHS; <a href="/entry/600880">600880</a>), <a href="#7" class="mim-tip-reference" title="Bucciarelli, P., Franchi, F., Alatri, A., Bettini, P., Moia, M. <strong>Budd-Chiari syndrome in a patient heterozygous for the G20210A mutation o the prothrombin gene. (Letter)</strong> Thromb. Haemost. 79: 445-446, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9493607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9493607</a>]" pmid="9493607">Bucciarelli et al. (1998)</a> identified heterozygosity for the 20210G-A substitution. His paternal grandmother had died at the age of 60 due to BDCHS, and his father, who was also heterozygous for the mutation, had had a myocardial infarction at age 55. <a href="#7" class="mim-tip-reference" title="Bucciarelli, P., Franchi, F., Alatri, A., Bettini, P., Moia, M. <strong>Budd-Chiari syndrome in a patient heterozygous for the G20210A mutation o the prothrombin gene. (Letter)</strong> Thromb. Haemost. 79: 445-446, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9493607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9493607</a>]" pmid="9493607">Bucciarelli et al. (1998)</a> excluded deficiencies of antithrombin, protein C, and protein S, as well as the presence of antiphospholipid syndrome and the factor V Leiden mutation. They suggested case-control studies to establish if carriers of the 20210G-A mutation have an increased risk of developing BDCHS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9493607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Oner, A. F., Arslan, S., Caksen, H., Ceylan, A. <strong>Budd-Chiari syndrome in a patient heterozygous for both factor V Leiden and the G20210A mutation on the prothrombin gene. (Letter)</strong> Thromb. Haemost. 82: 1366-1367, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10544935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10544935</a>]" pmid="10544935">Oner et al. (1999)</a> described Budd-Chiari syndrome in a patient heterozygous for both the 20210G-A mutation of F2 and the factor V Leiden mutation; heterozygosity for the factor V Leiden mutation is a known susceptibility factor for BDCHS. <a href="#42" class="mim-tip-reference" title="Oner, A. F., Arslan, S., Caksen, H., Ceylan, A. <strong>Budd-Chiari syndrome in a patient heterozygous for both factor V Leiden and the G20210A mutation on the prothrombin gene. (Letter)</strong> Thromb. Haemost. 82: 1366-1367, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10544935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10544935</a>]" pmid="10544935">Oner et al. (1999)</a> referred to the 20210G-A mutation by the abbreviation PM, presumably for 'prothrombin mutation.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10544935" 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>Susceptibility to Recurrent Pregnancy Loss</p><p><a href="#44" class="mim-tip-reference" title="Pihusch, R., Buchholz, T., Lohse, P., Rubsamen, H., Rogenhofer, N., Hasbargen, U., Hiller, E., Thaler, C. J. <strong>Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester.</strong> Am. J. Reprod. Immun. 46: 124-131, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11506076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11506076</a>] [<a href="https://doi.org/10.1111/j.8755-8920.2001.460202.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11506076">Pihusch et al. (2001)</a> studied clotting factors in 102 patients with 2 or more consecutive spontaneous abortions (RPRGL2; <a href="/entry/614390">614390</a>) compared to 128 women without miscarriage and found that heterozygosity for the 20210G-A mutation of prothrombin was more common in patients with abortions in the first trimester (p = 0.027; odds ratio, 8.5). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11506076" 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> rs121918483 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918483;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/rs121918483?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=rs121918483" 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=rs121918483" 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=RCV002468929" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002468929" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002468929</a>
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<p>This F2 variant is referred to as prothrombin Denver I.</p><p><a href="#40" class="mim-tip-reference" title="Montgomery, R. R., Corrigan, J. J., Clarke, S., Johnson, J. <strong>Prothrombin Denver: a new dysprothrombinemia. (Abstract)</strong> Circulation 62 (suppl. III): 279 only, 1980."None>Montgomery et al. (1980)</a> described a form of dysprothrombinemia (see <a href="/entry/613679">613679</a>) in a proband with a severe hemophilia-like bleeding disorder who was treated with weekly prophylactic prothrombin replacement. <a href="#32" class="mim-tip-reference" title="Lefkowitz, J. B., Haver, T., Clarke, S., Jacobson, L., Weller, A., Nuss, R., Manco-Johnson, M., Hathaway, W. E. <strong>The prothrombin Denver patient has two different prothrombin point mutations resulting in glu300-to-lys and glu309-to-lys substitutions.</strong> Brit. J. Haemat. 108: 182-187, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10651742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10651742</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2000.01810.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10651742">Lefkowitz et al. (2000)</a> found that the patient was a compound heterozygote for 2 mutations in the F2 gene: glu300-to-lys (E300K) and glu309-to-lys (E309K; <a href="#0011">176930.0011</a>). Factor II activity was 5 units/dl and factor II antigen was 21 units/dl. The functional defect was apparently in the activation of zymogen to enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10651742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<strong>.0011 DYSPROTHROMBINEMIA</strong>
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F2, GLU309LYS
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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> rs121918484 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918484;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/rs121918484?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=rs121918484" 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=rs121918484" 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=RCV002468930" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002468930" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002468930</a>
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<p>This F2 variant is referred to as prothrombin Denver II.</p><p>See (<a href="#0010">176930.0010</a>) and <a href="#32" class="mim-tip-reference" title="Lefkowitz, J. B., Haver, T., Clarke, S., Jacobson, L., Weller, A., Nuss, R., Manco-Johnson, M., Hathaway, W. E. <strong>The prothrombin Denver patient has two different prothrombin point mutations resulting in glu300-to-lys and glu309-to-lys substitutions.</strong> Brit. J. Haemat. 108: 182-187, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10651742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10651742</a>] [<a href="https://doi.org/10.1046/j.1365-2141.2000.01810.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10651742">Lefkowitz et al. (2000)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10651742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0012" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0012 DYSPROTHROMBINEMIA</strong>
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F2, ARG382HIS
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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> rs121918485 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918485;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/rs121918485?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=rs121918485" 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=rs121918485" 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=RCV002468931" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002468931" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002468931</a>
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<p><a href="#2" class="mim-tip-reference" title="Akhavan, S., Mannucci, P. M., Lak, M., Mancuso, G., Mazzucconi, M. G., Rocino, A., Jenkins, P. V., Perkins, S. J. <strong>Identification and three-dimensional structural analysis of nine novel mutations in patients with prothrombin deficiency.</strong> Thromb. Haemost. 84: 989-997, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11154146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11154146</a>]" pmid="11154146">Akhavan et al. (2000)</a> described a homozygous arg382-to-his (R382H) substitution in the prothrombin gene of an Iranian girl with dysprothrombinemia (see <a href="/entry/613679">613679</a>). The only symptoms were sporadic ecchymosis and 1 episode of buttock hematoma following a major trauma. A substitution in this residue had been identified in the compound heterozygous dysprothrombins Quick I (R382C; <a href="#0004">176930.0004</a>) and Corpus Christi. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11154146" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Akhavan, S., De Cristofaro, R., Peyvandi, F, Lavoretano, S., Landolfi, R., Mannucci, P. M. <strong>Molecular and functional characterization of a natural homozygous arg67-to-his mutation in the prothrombin gene of a patient with a severe procoagulant defect contrasting with a mild hemorrhagic phenotype.</strong> Blood 100: 1347-1353, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12149217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12149217</a>] [<a href="https://doi.org/10.1182/blood-2002-01-0243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12149217">Akhavan et al. (2002)</a> investigated the functional properties of the R382H mutant protein. Their experiments showed that the R382H substitution drastically affected both the procoagulant and the anticoagulant functions of thrombin as well as its inhibition by heparin cofactor II (<a href="/entry/142360">142360</a>). The mild hemorrhagic phenotype may be explained by abnormalities that ultimately counterbalance each other. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12149217" 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">rs121918486 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918486;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=rs121918486" 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=rs121918486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002468932" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002468932" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002468932</a>
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<p>This F2 variant is referred to as prothrombin Saint-Denis.</p><p>In a male newborn with dysprothrombinemia (see <a href="/entry/613679">613679</a>), <a href="#55" class="mim-tip-reference" title="Rouy, S., Vidaud, D., Alessandri, J.-L., Dautzenberg, M.-D., Venisse, L., Guillin, M.-C., Bezeaud, A. <strong>Prothrombin Saint-Denis: a natural variant with a point mutation resulting in asp to glu substitution at position 552 in prothrombin.</strong> Brit. J. Haemat. 132: 770-773, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16487178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16487178</a>] [<a href="https://doi.org/10.1111/j.1365-2141.2005.05920.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16487178">Rouy et al. (2006)</a> identified a new prothrombin variant, with a point mutation at nucleotide 20029 resulting in an asp552-to-glu (D552E) substitution. Prothrombin levels were reduced in each of 3 assays. The substitution did not affect the rate of prothrombin conversion to thrombin, but altered thrombin activity. Amino acid 552 had been involved in the allosteric transition, which is induced by sodium binding to thrombin. This was the first known amino acid substitution at this site to result in dysprothrombinemia. The male newborn was referred because of fetal pulmonary hypertension and left ventricular failure, which resolved spontaneously. The father and mother, who were first cousins, had a slight decrease in prothrombin activity and normal levels of prothrombin antigen. No abnormal bleeding was observed in the proband at birth or in the first 30 months of his life, and both parents were asymptomatic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16487178" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0014" class="mim-anchor"></a>
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<strong>.0014 HYPOPROTHROMBINEMIA</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> rs1227147475 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1227147475;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/rs1227147475?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=rs1227147475" 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=rs1227147475" 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=RCV000852095 OR RCV001678590" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000852095, RCV001678590" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000852095...</a>
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<p>In a patient with congenital prothrombin deficiency (<a href="/entry/613679">613679</a>) and severe bleeding tendency, <a href="#45" class="mim-tip-reference" title="Poort, S. R., Michiels, J. J., Reitsma, P. H., Bertina, R. M. <strong>Homozygosity for a novel missense mutation in the prothrombin gene causing a severe bleeding disorder.</strong> Thromb. Haemost. 72: 819-824, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7740448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7740448</a>]" pmid="7740448">Poort et al. (1994)</a> identified a homozygous A-to-G transition in exon 3 of the F2 gene, resulting in a tyr44-to-cys (Y44C) substitution. Laboratory studies showed factor II activity at about 2% and antigen levels at about 5%. Both parents were heterozygous for the mutation. Further family studies revealed complete cosegregation of the mutation with the prothrombin deficiency. Five homozygous brothers and sisters of the propositus were clinically affected with severe hemorrhages, including epistaxis, soft tissue, muscle, and joint bleedings in all, and severe menorrhagia in the 2 women. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7740448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Lancellotti, S., De Cristofaro, R. <strong>Congenital prothrombin deficiency.</strong> Semin. Thromb. Hemost. 35: 367-381, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19598065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19598065</a>] [<a href="https://doi.org/10.1055/s-0029-1225759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19598065">Lancellotti and De Cristofaro (2009)</a> noted that the Y44C mutation resulted from a 1305A-G change and affected the kringle-1 domain. The mutation was found in the family with hypoprothrombinemia reported by <a href="#64" class="mim-tip-reference" title="Van Creveld, S. <strong>Congenital idiopathic hypoprothrombinemia.</strong> Acta Paediat. Suppl. 43: 245-255, 1954.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13228032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13228032</a>] [<a href="https://doi.org/10.1111/j.1651-2227.1954.tb15475.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13228032">Van Creveld (1954)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19598065+13228032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0015 THROMBOPHILIA DUE TO THROMBIN DEFECT</strong>
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F2, ARG596LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387907201 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907201;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=rs387907201" 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=rs387907201" 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=RCV000024607" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024607" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024607</a>
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<p>In affected members of a Japanese family with recurrent thrombophilia due to thrombin defect (<a href="/entry/188050">188050</a>), <a href="#39" class="mim-tip-reference" title="Miyawaki, Y., Suzuki, A., Fujita, J., Maki, A., Okuyama, E., Murata, M., Takagi, A., Murate, T., Kunishima, S., Sakai, M., Okamoto, K., Matsushita, T., Naoe, T., Saito, H., Kojima, T. <strong>Thrombosis from a prothrombin mutation conveying antithrombin resistance.</strong> New Eng. J. Med. 366: 2390-2396, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22716977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22716977</a>] [<a href="https://doi.org/10.1056/NEJMoa1201994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22716977">Miyawaki et al. (2012)</a> identified a heterozygous 1787G-T transversion in the F2 gene, resulting in an arg596-to-leu (R596L) substitution within the sodium-binding region of thrombin and also in 1 of the antithrombin-binding sites. The mutation was not found in unaffected family members or in 100 control individuals. In vitro ELISA studies showed that the mutant prothrombin did not form a complex with antithrombin (SERPINC1; <a href="/entry/107300">107300</a>) even when heparin was added. A thrombin generation assay showed that the mutant prothrombin activity was lower than wildtype, but its inactivation in reconstituted plasma was exceedingly slow. <a href="#39" class="mim-tip-reference" title="Miyawaki, Y., Suzuki, A., Fujita, J., Maki, A., Okuyama, E., Murata, M., Takagi, A., Murate, T., Kunishima, S., Sakai, M., Okamoto, K., Matsushita, T., Naoe, T., Saito, H., Kojima, T. <strong>Thrombosis from a prothrombin mutation conveying antithrombin resistance.</strong> New Eng. J. Med. 366: 2390-2396, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22716977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22716977</a>] [<a href="https://doi.org/10.1056/NEJMoa1201994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22716977">Miyawaki et al. (2012)</a> concluded that although the procoagulant activity of mutant prothrombin was somewhat impaired due to disruption of the sodium-binding site, the antithrombin:thrombin complex was considerably impaired due to disruption of that binding site, causing continued facilitation of coagulation. The findings indicated that R596L was a gain-of-function mutation resulting in the resistance to antithrombin, and conferring susceptibility to thrombosis. The mutant variant was termed 'prothrombin Yukuhashi.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22716977" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Board1982" class="mim-tip-reference" title="Board, P. G., Coggan, M., Pidcock, M. E. <strong>Genetic heterogeneity of human prothrombin (FII).</strong> Ann. Hum. Genet. 46: 1-9, 1982.">Board et al. (1982)</a>; <a href="#Degen1983" class="mim-tip-reference" title="Degen, S. J. F., MacGillivray, R. T. A., Davie, E. W. <strong>Characterization of the complementary deoxyribonucleic acid and gene coding for human prothrombin.</strong> Biochemistry 22: 2087-2097, 1983.">Degen et al. (1983)</a>; <a href="#Henriksen1987" class="mim-tip-reference" title="Henriksen, R. A., Owen, W. G. <strong>Characterization of the catalytic defect in the dysthrombin, thrombin Quick.</strong> J. Biol. Chem. 262: 4664-4669, 1987.">Henriksen and Owen (1987)</a>; <a href="#Iwahana1992" class="mim-tip-reference" title="Iwahana, H., Yoshimoto, K., Shigekiyo, T., Shirakami, A., Saito, S., Itakura, M. <strong>Molecular and genetic analysis of a compound heterozygote for dysprothrombinemia of prothrombin Tokushima and hypoprothrombinemia.</strong> Am. J. Hum. Genet. 51: 1386-1395, 1992.">Iwahana et al. (1992)</a>
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Akhavan, S., De Cristofaro, R., Peyvandi, F, Lavoretano, S., Landolfi, R., Mannucci, P. M.
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<strong>Molecular and functional characterization of a natural homozygous arg67-to-his mutation in the prothrombin gene of a patient with a severe procoagulant defect contrasting with a mild hemorrhagic phenotype.</strong>
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Blood 100: 1347-1353, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12149217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12149217</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12149217" 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-2002-01-0243" target="_blank">Full Text</a>]
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Akhavan, S., Mannucci, P. M., Lak, M., Mancuso, G., Mazzucconi, M. G., Rocino, A., Jenkins, P. V., Perkins, S. J.
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<strong>Identification and three-dimensional structural analysis of nine novel mutations in patients with prothrombin deficiency.</strong>
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Thromb. Haemost. 84: 989-997, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11154146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11154146</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11154146" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Banfield, D. K., MacGillivray, R. T. A.
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<strong>Partial characterization of vertebrate prothrombin cDNAs: amplification and sequence analysis of the B chain of thrombin from nine different species.</strong>
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Proc. Nat. Acad. Sci. 89: 2779-2783, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1557383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1557383</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1557383" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bertina, R. M., Rosendaal, F. R.
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<strong>Venous thrombosis - the interaction of genes and environment. (Letter)</strong>
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New Eng. J. Med. 338: 1840-1841, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9632453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9632453</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9632453" 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/NEJM199806183382510" target="_blank">Full Text</a>]
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<a id="Board1982" class="mim-anchor"></a>
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Board, P. G., Coggan, M., Pidcock, M. E.
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<strong>Genetic heterogeneity of human prothrombin (FII).</strong>
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Ann. Hum. Genet. 46: 1-9, 1982.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7103409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7103409</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7103409" 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/10.1111/j.1469-1809.1982.tb00689.x" target="_blank">Full Text</a>]
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Board, P. G., Shaw, D. C.
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<strong>Determination of the amino acid substitution in human prothrombin type 3 (157 glu-to-lys) and the localization of a third thrombin cleavage site.</strong>
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Brit. J. Haemat. 54: 245-254, 1983.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6405779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6405779</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6405779" 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/10.1111/j.1365-2141.1983.tb02092.x" target="_blank">Full Text</a>]
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Bucciarelli, P., Franchi, F., Alatri, A., Bettini, P., Moia, M.
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<strong>Budd-Chiari syndrome in a patient heterozygous for the G20210A mutation o the prothrombin gene. (Letter)</strong>
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Thromb. Haemost. 79: 445-446, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9493607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9493607</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9493607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Casas, J. P., Hingorani, A. D., Bautista, L. E., Sharma, P.
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<strong>Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18000 cases and 58000 controls.</strong>
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Arch. Neurol. 61: 1652-1662, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15534175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15534175</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15534175" 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/10.1001/archneur.61.11.1652" target="_blank">Full Text</a>]
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Celikel, R., McClintock, R. A., Roberts, J. R., Mendolicchio, G. L., Ware, J., Varughese, K. I., Ruggeri, Z. M.
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<strong>Modulation of alpha-thrombin function by distinct interactions with platelet glycoprotein Ib-alpha.</strong>
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Science 301: 218-221, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12855810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12855810</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12855810" 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/s0016-5085(99)70238-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199909093411104" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1046/j.1365-2141.2001.02827.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1021/bi00393a033" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1021/bi00278a008" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1083917" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1046/j.1365-2141.1999.01149.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1378/chest.121.1.286" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13228032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13228032</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13228032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
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|
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[<a href="https://doi.org/10.1111/j.1651-2227.1954.tb15475.x" 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>
|
|
<a id="65" class="mim-anchor"></a>
|
|
<a id="Zivelin2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Zivelin, A., Mor-Cohen, R., Kovalsky, V., Kornbrot, N., Conard, J., Peyvandi, F., Kyrle, P. A., Bertina, R., Peyvandi, F., Emmerich, J., Seligsohn, U.
|
|
<strong>Prothrombin 20210G-A is an ancestral prothrombotic mutation that occurred in whites approximately 24,000 years ago.</strong>
|
|
Blood 107: 4666-4668, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16493002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16493002</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16493002" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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[<a href="https://doi.org/10.1182/blood-2005-12-5158" 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>
|
|
<a id="66" class="mim-anchor"></a>
|
|
<a id="Zivelin1998" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Zivelin, A., Rosenberg, N., Faier, S., Kornbrot, N., Peretz, H., Mannhalter, C., Horellou, M. H., Seligsohn, U.
|
|
<strong>A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene.</strong>
|
|
Blood 92: 1119-1124, 1998.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9694698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9694698</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9694698" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</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>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Cassandra L. Kniffin - updated : 6/20/2012
|
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</span>
|
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</div>
|
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</div>
|
|
<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">
|
|
<span class="mim-text-font">
|
|
Marla J. F. O'Neill - updated : 12/13/2011<br>Carol A. Bocchini - updated : 1/5/2011<br>Cassandra L. Kniffin - updated : 1/3/2011<br>Victor A. McKusick - updated : 9/28/2006<br>Victor A. McKusick - updated : 6/9/2006<br>Cassandra L. Kniffin - updated : 6/10/2005<br>Ada Hamosh - updated : 1/5/2004<br>Victor A. McKusick - updated : 10/16/2002<br>Victor A. McKusick - updated : 10/8/2002<br>Victor A. McKusick - updated : 11/7/2001<br>Victor A. McKusick - updated : 9/20/2001<br>Ada Hamosh - updated : 7/13/2001<br>Victor A. McKusick - updated : 2/26/2001<br>Victor A. McKusick - updated : 6/7/2000<br>Victor A. McKusick - updated : 2/24/2000<br>Victor A. McKusick - updated : 2/1/2000<br>Victor A. McKusick - updated : 1/10/2000<br>George E. Tiller - updated : 11/16/1999<br>Victor A. McKusick - updated : 7/13/1999<br>Ada Hamosh - updated : 5/18/1999<br>Victor A. McKusick - updated : 3/25/1999<br>Victor A. McKusick - updated : 9/29/1998<br>Victor A. McKusick - updated : 8/21/1998<br>Victor A. McKusick - updated : 6/25/1998<br>Victor A. McKusick - updated : 6/10/1998
|
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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">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
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</span>
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Victor A. McKusick : 6/2/1986
|
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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>
|
|
</span>
|
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/22/2022
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</span>
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</div>
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</div>
|
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<div class="row collapse" id="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 : 06/04/2019<br>alopez : 05/31/2018<br>alopez : 09/07/2016<br>carol : 08/30/2016<br>carol : 01/29/2015<br>carol : 6/20/2012<br>ckniffin : 6/20/2012<br>carol : 3/1/2012<br>carol : 2/28/2012<br>alopez : 12/13/2011<br>carol : 7/19/2011<br>carol : 4/8/2011<br>carol : 4/7/2011<br>carol : 2/11/2011<br>terry : 1/5/2011<br>carol : 1/5/2011<br>carol : 1/5/2011<br>carol : 1/4/2011<br>carol : 1/4/2011<br>ckniffin : 1/3/2011<br>carol : 11/18/2009<br>ckniffin : 11/11/2009<br>alopez : 6/16/2009<br>terry : 5/4/2009<br>carol : 10/8/2008<br>carol : 9/29/2008<br>carol : 10/3/2006<br>terry : 9/28/2006<br>alopez : 7/5/2006<br>terry : 6/9/2006<br>carol : 6/13/2005<br>ckniffin : 6/10/2005<br>carol : 3/17/2004<br>cwells : 1/7/2004<br>terry : 1/5/2004<br>tkritzer : 11/19/2002<br>tkritzer : 11/1/2002<br>tkritzer : 10/22/2002<br>terry : 10/16/2002<br>carol : 10/16/2002<br>tkritzer : 10/14/2002<br>terry : 10/8/2002<br>carol : 11/26/2001<br>mcapotos : 11/16/2001<br>mcapotos : 11/16/2001<br>terry : 11/7/2001<br>carol : 10/12/2001<br>mcapotos : 9/27/2001<br>mcapotos : 9/21/2001<br>terry : 9/20/2001<br>alopez : 8/2/2001<br>alopez : 7/16/2001<br>terry : 7/13/2001<br>mcapotos : 3/6/2001<br>mcapotos : 3/2/2001<br>terry : 2/26/2001<br>mcapotos : 2/13/2001<br>carol : 7/6/2000<br>mcapotos : 6/28/2000<br>mcapotos : 6/23/2000<br>terry : 6/7/2000<br>alopez : 3/22/2000<br>alopez : 3/22/2000<br>alopez : 3/21/2000<br>mcapotos : 3/17/2000<br>mcapotos : 3/1/2000<br>terry : 2/24/2000<br>mcapotos : 2/14/2000<br>mcapotos : 2/9/2000<br>terry : 2/1/2000<br>mcapotos : 1/20/2000<br>mcapotos : 1/19/2000<br>terry : 1/10/2000<br>alopez : 11/16/1999<br>carol : 7/23/1999<br>jlewis : 7/21/1999<br>terry : 7/13/1999<br>alopez : 5/24/1999<br>terry : 5/18/1999<br>mgross : 4/2/1999<br>mgross : 3/31/1999<br>terry : 3/25/1999<br>terry : 10/1/1998<br>carol : 9/30/1998<br>terry : 9/29/1998<br>carol : 8/24/1998<br>terry : 8/21/1998<br>dholmes : 7/22/1998<br>alopez : 6/26/1998<br>terry : 6/25/1998<br>terry : 6/11/1998<br>dholmes : 6/10/1998<br>terry : 8/8/1997<br>carol : 6/20/1997<br>mark : 6/14/1997<br>mark : 6/25/1996<br>mimadm : 2/25/1995<br>davew : 8/19/1994<br>terry : 7/15/1994<br>warfield : 3/11/1994<br>carol : 7/13/1993<br>carol : 1/21/1993
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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>
|
|
<h3>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 176930
|
|
</span>
|
|
</h3>
|
|
</div>
|
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|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
COAGULATION FACTOR II; F2
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div >
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
THROMBIN<br />
|
|
PROTHROMBIN<br />
|
|
FACTOR II
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
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</div>
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|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: F2</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
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|
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|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
|
|
<strong>SNOMEDCT:</strong> 33297000;
|
|
|
|
|
|
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|
|
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|
</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
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|
|
|
|
<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 11p11.2
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 11:46,719,213-46,739,506 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<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="5">
|
|
<span class="mim-font">
|
|
11p11.2
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Pregnancy loss, recurrent, susceptibility to, 2}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
614390
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Stroke, ischemic, susceptibility to}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
601367
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Multifactorial
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Dysprothrombinemia
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613679
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hypoprothrombinemia
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613679
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Thrombophilia 1 due to thrombin defect
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
188050
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>The F2 gene encodes coagulation factor II (EC 3.4.21.5), or prothrombin, a vitamin K-dependent glycoprotein synthesized in the liver as an inactive zymogen. Prothrombin is activated to the serine protease thrombin by factor Xa (F10; 613872) in the presence of phospholipids, calcium, and factor Va (F5; 612309). The activated thrombin enzyme plays an important role in hemostasis and thrombosis: it converts fibrinogen (134820) to fibrin for blood clot formation, stimulates platelet aggregation, and activates coagulation factors V, VIII (F8; 300841), and XIII (F13A1; 134570). Thrombin also inhibits coagulation by activating protein C (PROC; 612283) (summary by Lancellotti and De Cristofaro, 2009). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Degen and Davie (1987) determined the nucleotide sequence of the human prothrombin gene, which encodes a 622-residue pre-propeptide with a molecular mass of about 70 kD. The mature circulating protein has 579 residues. The prothrombin protein contains 5 domains: the propeptide (residues -43 to -1), the Gla domain (residues 1 to 40), a kringle domain (residues 41 to 155), a kringle-2 domain (residues 156 to 271), and a serine protease domain (residues 272 to 579). The prothrombin protein undergoes several cleavage events to generate the active enzyme alpha-thrombin, which is composed of a light (alpha) and heavy (beta) chain covalently linked by a disulfide bond (summary by Lancellotti and De Cristofaro, 2009). </p><p>Degen et al. (1990) cloned cDNAs for mouse coagulation factor II and compared the gene and predicted protein structure with that of human prothrombin. </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>Degen and Davie (1987) determined that the prothrombin gene contains 14 exons and spans about 21 kb. The gene contains 30 Alu repeats and 2 Kpn repeats, which constitute about 40% of the gene. </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>Royle et al. (1987) assigned the gene for human prothrombin (F2) to chromosome 11p11-q12 by analysis of a panel of somatic cell hybrid DNAs and by in situ hybridization, using both cDNA and genomic probes. </p><p>Degen et al. (1990) mapped the mouse F2 gene to chromosome 2, about 1.8 map units proximal to the catalase locus. </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>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Celikel et al. (2003) determined that the structure of platelet GP1BA (606672) bound to thrombin at 2.3-angstrom resolution and defined 2 sites that bind to exosite II and exosite I of 2 distinct alpha-thrombin molecules, respectively. GP1BA occupancy may be sequential, as the site binding to alpha-thrombin exosite I appears to be cryptic in the unoccupied receptor but exposed when a first thrombin molecule is bound through exosite II. Celikel et al. (2003) suggested that these interactions may modulate alpha-thrombin function by mediating GP1BA clustering and cleavage of protease-activator receptors, which promote platelet activation, while limiting fibrinogen clotting through blockade of exosite I. </p><p>Dumas et al. (2003) independently determined the crystal structure of the GP1BA-thrombin complex at 2.6-angstrom resolution. They found that in the crystal lattice, the periodic arrangement of GP1BA-thrombin complexes mirrors a scaffold that could serve as a driving force for tight platelet adhesion. </p><p>Kroh et al. (2009) found that von Willebrand factor-binding protein (VWFBP), which is secreted by Staphylococcus aureus, is a potent nonenzymatic conformational activator of prothrombin. VWFBP was found to share homology with staphylocoagulase, another protein secreted by Staphylococcus aureus that can activate prothrombin. However, the mechanism of VWFBP activation of prothrombin was different from that of staphylocoagulase, with VWFBP showing weaker affinity for prothrombin and resulting in a slow conformational change with a specific need for binding of the substrate fibrinogen to complete the process. The findings suggested a unique mechanism for fibrin deposition during S. aureus endocarditis. </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>Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).</p><p><strong><em>Congenital Prothrombin Deficiency and Dysprothrombinemia</em></strong></p><p>
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|
Congenital prothrombin deficiency, also known as hypoprothrombinemia (613679), is a rare autosomal recessive disorder characterized by severe bleeding manifestations and decreased prothrombin antigen levels and activity to below 10% of normal values. Dysprothrombinemia, which is characterized by normal antigen levels but a dysfunctional prothrombin molecule, shows a more variable level in bleeding tendency, and there is often a good correlation between the levels of prothrombin activity and clinical severity. Akhavan et al. (2002) stated that 32 molecular defects in prothrombin had been identified. Complete prothrombin deficiency, or aprothombinemia, is believed to be incompatible with life (review by Meeks and Abshire, 2008). </p><p>The allelic variants causing dysprothrombinemia are usually indicated according to the city or area where they were described for the first time: see, e.g., prothrombin Barcelona (176930.0002) and prothrombin Tokushima (176930.0003). The abnormalities are usually caused by a defect in activation of the protease, such as prothrombin Barcelona, or a defect in the protease itself, such as prothrombin Quick (176930.0004; 176930.0005) and prothrombin Tokushima (reviews by Girolami et al., 1998 and Lancellotti and De Cristofaro, 2009). </p><p><strong><em>Thrombophilia</em></strong></p><p>
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|
Poort et al. (1996) described a common genetic variation in the 3-prime untranslated region of the prothrombin gene that is associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis (THPH1; 188050): a 20210G-A transition (176930.0009). They found this single base substitution in 18% of probands of thrombophilic families, 6% of unselected consecutive patients with deep vein thrombosis, and 2% of healthy controls. Rosendaal et al. (1997) found that the mutation was associated with a 4-fold increased risk of myocardial infarction in women, while among men the risk was increased 1.5-fold (Doggen et al., 1998). </p><p>Martinelli et al. (1998) found that the 20210G-A mutation in the prothrombin gene (176930.0009) and the factor V Leiden mutation (612309.0001) are associated with 'idiopathic' cerebral vein thrombosis. The use of oral contraceptives was also strongly and independently associated with the disorder. The presence of both the prothrombin gene mutation and oral contraceptive use raised the risk of cerebral vein thrombosis further. The F2 and F5 mutations had previously been known to be common genetic determinants of deep vein thrombosis of the lower extremities. Cerebral vein thrombosis is a frightening event because of the severity of the clinical manifestations and the high mortality rate, estimated to be 5 to 30%. Clinically, cerebral vein thrombosis presents with a wide range of symptoms, including headache, focal deficits (motor or sensory), dysphasia, seizures, and impaired consciousness. The findings of Martinelli et al. (1998) represent a prime example of the interaction of endogenous (genetic) and exogenous factors in causation of disease (Bertina and Rosendaal, 1998). </p><p>De Stefano et al. (1999) examined the relative risk of recurrent deep venous thrombosis using a proportional-hazards model. The authors found that while patients who were heterozygous for factor V Leiden had a risk of recurrent deep venous thrombosis that was similar to that among patients who had no known mutations in either factor II or factor V, patients who were heterozygous for both factor V Leiden and prothrombin 20210G-A had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. </p><p>The factor V Leiden mutation (612309.0001) and the 20210G-A mutation in the prothrombin gene (176930.0009) are the most frequent abnormalities associated with venous thromboembolism. Martinelli et al. (2000) compared the prevalence and incidence rate of venous thromboembolism in relatives with either of these 2 mutations or both. The study population included 1,076 relatives of probands with the prothrombin gene mutation, factor V Leiden, or both, who underwent screening for inherited thrombophilia and were found to be carriers of single mutations or double mutations or who were noncarriers. The prevalence of venous thromboembolism was 5.7% in relatives with the prothrombin gene mutation, 7.8% in those with factor V Leiden, 17.1% in those with both mutations, and 2.5% in noncarriers. Annual incidences of thrombosis were 0.13%, 0.19%, 0.42%, and 0.066%, respectively. The relative risk of thrombosis was 2 times higher in carriers of the prothrombin gene mutation, 3 times higher in those with factor V Leiden, and 6 times higher in double carriers than in noncarriers. The incidence of venous thromboembolism in carriers of the prothrombin gene mutation was slightly lower than that observed in carriers of factor V Leiden, whereas in carriers of both mutations it was 2 or 3 times higher. From these findings, Martinelli et al. (2000) concluded that lifelong primary anticoagulant prophylaxis of venous thromboembolism is not needed in asymptomatic carriers of single or double mutations. Anticoagulant prophylaxis seems to be indicated only when transient risk factors for thrombosis coexist with mutations. </p><p>In affected members of a Japanese family with recurrent thrombophilia, Miyawaki et al. (2012) identified a heterozygous mutation in the F2 gene (R596L; 176930.0015). The family had originally been reported by Sakai et al. (2001). In vitro ELISA studies showed that the mutant prothrombin did not form a complex with antithrombin (SERPINC1; 107300) even when heparin was added. A thrombin generation assay showed that the mutant prothrombin activity was lower than wildtype, but its inactivation in reconstituted plasma was exceedingly slow. Miyawaki et al. (2012) concluded that although the procoagulant activity of the R596L mutant prothrombin was somewhat impaired, the antithrombin:thrombin complex was considerably impaired, causing continued facilitation of coagulation. The findings indicated that R596L was a gain-of-function mutation resulting in the resistance to antithrombin, and conferring susceptibility to thrombosis. The mutant variant was termed 'prothrombin Yukuhashi.' </p><p><strong><em>Susceptibility to Recurrent Pregnancy Loss</em></strong></p><p>
|
|
Pihusch et al. (2001) studied clotting factors in 102 patients with 2 or more consecutive spontaneous abortions (RPRGL2; 614390) compared to 128 women without miscarriage and found that heterozygosity for the 20210G-A mutation of prothrombin (176930.0009) was more common in patients with abortions in the first trimester (p = 0.027; odds ratio, 8.5). Noting that in addition to fibrin generation, thrombin also activates tissue components represented in the placenta and induces cellular responses, Pihusch et al. (2001) suggested that increased prothrombin levels might affect placental function by influencing pivotal mechanisms such as cell adhesion, smooth muscle proliferation, and vasculogenesis. </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>Several observations suggest that prothrombin may serve a broader physiologic role than simply stemming blood loss, including the identification of multiple G protein-coupled, thrombin-activated receptors, and the well-documented mitogenic activity of thrombin in in vitro test systems. To explore further the physiologic roles of prothrombin in vivo, Sun et al. (1998) generated prothrombin-deficient mice by knockout techniques. Inactivation of the F2 gene led to partial embryonic lethality with more than half of the F2 -/- embryos dying between embryonic days 9.5 and 11.5. Bleeding into the yolk sac cavity and varying degrees of tissue necrosis were observed in many of the F2 -/- embryos within this gestational time frame. At least one-quarter of the F2 -/- mice survived to term, but they ultimately developed fatal hemorrhagic events and died within a few days of birth. The study demonstrated that F2 is important in maintaining vascular integrity during development as well as in postnatal life. </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">
|
|
<strong>ALLELIC VARIANTS</strong>
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</span>
|
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<strong>15 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0001 PROTHROMBIN TYPE 3</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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F2, GLU157LYS
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<br />
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SNP: rs62623459,
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gnomAD: rs62623459,
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ClinVar: RCV000014229, RCV000994617, RCV001108917, RCV001108918, RCV001794445
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>Board and Shaw (1983) showed that prothrombin type 3 is due to a glu157-to-lys (E157K) substitution in the F2 gene. This was the first identification of the specific change in a variant prothrombin, isolated from individuals heterozygous for prothrombin type 3. This substitution explained the relatively slow electrophoretic mobility of prothrombin type 3 compared to wildtype at alkaline pH. </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>.0002 DYSPROTHROMBINEMIA</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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F2, ARG271CYS
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<br />
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SNP: rs121918477,
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gnomAD: rs121918477,
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ClinVar: RCV002468924
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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 F2 variant is referred to as prothrombin Barcelona.</p><p>In a patient with normal prothrombin antigen levels, but low prothrombin coagulant activity (see 613679) (Rabiet et al., 1979), Rabiet et al. (1986) found that the defect was due to an arg271-to-cys (R271C) substitution in the F2 gene. The peptide bond between arg271 and thr272 is one of 2 sites of cleavage by factor Xa, indicating that activation of the variant Barcelona prothrombin protein to functional thrombin was impaired. </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>.0003 DYSPROTHROMBINEMIA</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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F2, ARG418TRP
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<br />
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|
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SNP: rs121918478,
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gnomAD: rs121918478,
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|
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ClinVar: RCV002468925
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>This F2 variant is referred to as prothrombin Tokushima.</p><p>In a 10-year-old Japanese girl who was compound heterozygous for dysprothrombinemia (see 613679) and hypoprothrombinemia, Miyata et al. (1987) identified a heterozygous 9490T-to-C transition in the F2 gene, resulting in an arg418-to-trp (R418W) substitution on the maternal allele. The patient had originally been reported by Inomoto et al. (1987), who determined that the prothrombin variant showed about 22% clotting activity and reduced platelet aggregating activity, suggesting a defect in the catalytic region (Lancellotti and De Cristofaro, 2009). Shirakami et al. (1983) and Shirakami and Kawauchi (1984) concluded from study of this pedigree that the proband was a 'double heterozygote' for a dysprothrombinemia variant (R418W), inherited from the mother, and a hypoprothrombinemia (613679) variant, inherited from the father. Indeed, Iwahana et al. (1992) determined that the hypoprothombinemia variant inherited from the father was a 1-bp insertion (4177insT; 176930.0008). </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>.0004 DYSPROTHROMBINEMIA</strong>
|
|
</span>
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</h4>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
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|
F2, ARG382CYS
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<br />
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|
|
SNP: rs121918479,
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|
|
|
|
|
|
|
ClinVar: RCV002468926
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|
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|
|
|
</span>
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</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This F2 variant is referred to as prothrombin Quick I.</p><p>A patient with dysprothrombinemia (see 613679) originally studied by Quick et al. (1955), Quick and Hussey (1962), and Owen et al. (1978) was later found to be compound heterozygous for 2 defective alleles in the F2 gene. Henriksen and Mann (1988) identified a heterozygous C-to-T transition resulting in an arg382-to-cys (R382C) substitution, and Henriksen and Mann (1989) identified a heterozygous G-to-T transversion resulting in a gly558-to-val (G558V; 176930.0005) substitution. The patient had less than 2% of normal prothrombin activity. Laboratory studies by Henriksen and Mann (1988, 1989) showed that both variants resulted in a structural change in the catalytic region causing defective interaction with fibrinogen. </p><p>Banfield and MacGillivray (1992) found that the arginine residue at codon 382 is conserved in 11 species ranging from the human to the gecko (a lizard), the newt, and fish, including rainbow trout, sturgeon, and the hagfish. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 DYSPROTHROMBINEMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
F2, GLY558VAL
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<br />
|
|
|
|
SNP: rs121918480,
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|
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|
|
|
|
|
ClinVar: RCV002468927
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|
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|
|
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</span>
|
|
</div>
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|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>This F2 variant is referred to as prothrombin Quick II.</p><p>See 176930.0004 and Henriksen and Mann (1989). </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0006 DYSPROTHROMBINEMIA</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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F2, MET337THR
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<br />
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SNP: rs121918481,
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|
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ClinVar: RCV002468928
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>This F2 variant is referred to as prothrombin Himi I.</p><p>In a girl with dysprothrombinemia (see 613679), Morishita et al. (1992) found a congenitally dysfunctional form of prothrombin, called prothrombin Himi, which was associated with reduced fibrinogen clotting activity, although it retained full hydrolytic activity toward synthetic substrates. Because previous findings suggested that the functional defect of prothrombin Himi was caused by an abnormality in the thrombin portion of the protein, Morishita et al. (1992) amplified the genomic DNA regions corresponding to exons 8 through 14 and applied single-strand conformation polymorphism analysis. Two variant conformers in exon 10 were identified in the proband with this variant: an 8751T-C transition resulting in a met337-to-thr (M337T) substitution inherited from the father, and an 8904G-A transition resulting in an arg388-to-his (R388H; 176930.0007) substitution inherited from the mother. </p>
|
|
</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>.0007 DYSPROTHROMBINEMIA PROTHROMBIN HIMI-II</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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F2, ARG388HIS
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<br />
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SNP: rs121918482,
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gnomAD: rs121918482,
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ClinVar: RCV000014235
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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 F2 variant is referred to as prothrombin Himi II.</p><p>See 176930.0006 and Morishita et al. (1992). </p>
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</span>
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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>.0008 HYPOPROTHROMBINEMIA</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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F2, 1-BP INS, 4177T
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<br />
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SNP: rs387906522,
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gnomAD: rs387906522,
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ClinVar: RCV000014236
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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 Japanese girl who was compound heterozygous for hypoprothrombinemia (613679) and dysprothrombinemia, Iwahana et al. (1992) demonstrated a heterozygous 1-bp insertion (4177insT) in exon 6 of the F2 gene inherited from her father. This defect was the basis of the hypoprothrombinemia. The resulting frameshift mutation caused both an altered amino acid sequence from codon 114 and a premature termination codon (TGA) at codon 174 in exon 7. Because exon 7 encodes the kringle-2 domain preceding the thrombin sequence, the frameshift led to the null prothrombin phenotype. The girl was compound heterozygous for 4177insT and an R418W (176930.0003) substitution, which was the basis of the dysprothrombinemia (see 613679). </p>
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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>.0009 THROMBOPHILIA DUE TO THROMBIN 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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STROKE, ISCHEMIC, SUSCEPTIBILITY TO, INCLUDED<br />
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PREGNANCY LOSS, RECURRENT, SUSCEPTIBILITY TO, 2, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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F2, 20210G-A
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<br />
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SNP: rs1799963,
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gnomAD: rs1799963,
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ClinVar: RCV000014237, RCV000014238, RCV000022729, RCV000205022, RCV000826090, RCV001091960, RCV001794446, RCV002468555, RCV005042047
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</span>
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</div>
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<span class="mim-text-font">
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<p>Rosendaal et al. (1998) presented data from 11 centers and 9 countries, representing a total of 5,527 tested individuals. Among these, 111 heterozygous carriers of the 20210A mutation were found, yielding an overall prevalence of 2.0%. In southern Europe, the prevalence was 3.0%, nearly twice as high as the prevalence in northern Europe (1.7%). The prothrombin variant appeared to be rare in individuals of Asian and African descent. </p><p>To discern whether the 20210G-A polymorphism originated from a single or recurrent mutation event, Zivelin et al. (1998) determined allele frequencies of 4 dimorphisms spanning 16 of 21 kb of the factor II gene in 133 unrelated Caucasian subjects of Jewish, Austrian, and French origins who bore factor II 20210A (10 homozygotes and 123 heterozygotes) and 110 Caucasian controls. Remarkable differences in the allele frequencies for each dimorphism were observed between the study groups (p = 0.0007 or less), indicating strong linkage disequilibrium and suggesting a founder effect. Indeed, a founder haplotype was present in 68% of 20210A mutant alleles and in only 34% of 20210G normal alleles (p less than 0.0001). These data strongly supported a single origin for the factor II polymorphism. Because the polymorphism is rare or absent in non-Caucasian populations, it probably occurred after divergence of Africans from non-Africans and of Caucasoids from Mongoloid subpopulations. </p><p>Rees et al. (1999) analyzed samples from 22 different non-European countries and found that the prothrombin 20210G-A variant, like factor V Leiden (612309.0001), is rare outside Europe. Of 1,811 non-Europeans tested, they found only 1 individual, in India, who had the mutation in heterozygous state. </p><p>Zivelin et al. (2006) analyzed the frequencies of 5 SNPs and 9 microsatellites flanking the prothrombin gene in 88 homozygotes for 20210A and 66 homozygotes for 20210G. For estimating the age of the prothrombin 20210G-A mutation, they analyzed linkage disequilibrium between the mutation and the multiple markers that had been assessed. The analysis yielded an age estimate of 23,720 years. A similar analysis was performed for factor V Leiden (612309.0001) yielding an age estimate of 21,340 years. The occurrence of the 2 mutations in whites toward the end of the last glaciation and their presently wide distribution in whites suggested selective evolutionary advantages for which some evidence was reported (diminished blood loss) or is controversial (protection against infections). The selected disadvantage from thrombosis is unlikely because until recent centuries humans did not live long enough to manifest a meaningful incidence of thrombosis. </p><p>Thrombophilia</p><p>Poort et al. (1996) found that a common genetic 20210G-A transition in the 3-prime untranslated region of the prothrombin gene (Degen and Davie, 1987) was associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis (THPH1; 188050). The SNP was found in 18% of probands of families with thrombosis, 6% of unselected consecutive patients with deep vein thrombosis, and 2% of healthy controls. Rosendaal et al. (1997) found that the mutation was associated with a 4-fold increased risk of myocardial infarction in women, while among men the risk was increased 1.5-fold (Doggen et al., 1998). </p><p>Franco et al. (1999) found a frequency of the 20210A allele of 1% in a 400-member healthy control population and 2.7% in 263 patients with proven premature atherosclerotic disease. All heterozygotes in the patient group were found to have had a myocardial infarction. In addition, the data provided evidence for an association of the mutation with excessive thrombin generation, which may contribute to the understanding of its role in venous and arterial disease. </p><p>Chamouard et al. (1999) studied the frequency of the factor II 20210G-A mutation in 10 white European patients with idiopathic portal vein thrombosis. They studied 5 women and 5 men; mean age was 50.4 years. The frequency of the 20210G-A mutation was found to be 40% in idiopathic portal vein thrombosis compared with 4.8% in controls or patients with nonidiopathic portal vein thrombosis or deep vein thrombosis. The frequency of the factor V Leiden mutation (612309.0001) was similar in subjects with portal vein thrombosis and in controls but was increased in patients with deep vein thrombosis. </p><p>De Stefano et al. (1999) found that patients who were heterozygous for both factor V Leiden (1691G-A; 612309.0001) and prothrombin 20210G-A had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. Patients who were heterozygous for factor V Leiden had a risk of recurrent deep venous thrombosis that was similar to that among patients who had no known mutations in either factor II or factor V. </p><p>In a Spanish family, Corral et al. (1999) identified 3 subjects homozygous for the 20210A prothrombin mutation who additionally were heterozygous for factor V Leiden. The combination of the 2 mutations increased the risk of developing venous thrombotic episodes at an earlier age. However, even in association with factor V Leiden, the homozygous condition of the 20210A prothrombin mutation required additional risk factors to induce a thrombotic event. </p><p>Humpert et al. (1999) screened 384 type 1 diabetic patients for the 20210G-A prothrombin polymorphism and detected the variant in 9 patients. There was no increase in the incidence of coronary heart disease, nephropathy, or retinopathy among diabetic patients carrying the 20210G-A polymorphism. </p><p>Meyer et al. (1999) described a method for simultaneously genotyping for factor V Leiden and the prothrombin 20210G-A variant by a multiplex PCR-SSCP assay on whole blood. Prohaska et al. (1999) studied 284 patients with angiographically confirmed coronary artery disease for the presence of the 20210G-A polymorphism of the prothrombin gene and compared them with 340 healthy controls. The prevalence of the mutation was similar in both groups. There was a mild increase in the frequency of the mutation in a group of 294 venous thrombosis patients compared with the healthy controls (odds ratio, 2.90; 95% CI, 1.25-6.9). </p><p>One of the main factors of sudden hearing impairment, vestibular disturbance (tinnitus), is generally thought to be an acute labyrinthine ischemia; the most common mechanism of sudden hearing loss appears to be impaired cochlear blood circulation. Mercier et al. (1999) provided evidence that the 20210A allele of the prothrombin gene is a risk factor for perception deafness. Among 368 patients (median age, 41 years) with spontaneous deep vein thrombosis, 18 (12 women and 6 men, 38 to 69 years of age) had also suffered from acute unilateral hearing impairment. Six of the 18 were heterozygous for the 20210A allele. In a group of 395 nonthrombotic consecutive patients studied in the same laboratory for hemorrhagic symptoms or thrombocytopenia over the same period of time, 4 had acute unilateral perception deafness; of 395 nonthrombotic and nonhemorrhagic sex- and age-matched controls, 6 had acute unilateral perception deafness. </p><p>Souto et al. (1999) reported a family illustrating the complexity of thrombotic disease in relation to the 20210A variant. The pedigree was ascertained through a proband with idiopathic thrombophilia. The family members who had a history of thromboembolism were heterozygous carriers of the 20210A variant. In addition, 4 relatives who were heterozygous as well as 2 who were homozygous for the 20210A allele failed to show clinical manifestations. The 2 homozygotes were 51 and 19 years old. </p><p>Gehring et al. (2001) demonstrated that the 20210G-A mutation does not affect the amount of pre-mRNA, the site of 3-prime end cleavage, or the length of poly(A) tail of the mature mRNA. Rather, Gehring et al. (2001) demonstrated that the physiologic F2 3-prime end cleavage signal is inefficient and that F2 20210G-A represents a gain-of-function mutation, causing increased cleavage site recognition, increased 3-prime end processing, and increased mRNA accumulation and protein synthesis. Enhanced mRNA 3-prime end formation efficiency emerges as a novel principle causing a genetic disorder and explains the role of the F2 20210G-A mutation in the pathogenesis of thrombophilia. Gehring et al. (2001) concluded that their work illustrates the pathophysiologic importance of quantitatively minor aberrations of RNA metabolism. </p><p>Although the 20210G-A mutation in heterozygous state carries an increased risk of a first venous thromboembolic episode, De Stefano et al. (2001) found that the risk of spontaneous recurrent venous thromboembolism was similar to that in patients with normal genotype. They concluded that carriers of the prothrombin mutation should be treated with oral anticoagulants after a first deep venous thrombosis for a similar length of time as patients with a normal genotype. </p><p>Laczika et al. (2002) described a 19-year-old woman with the joint occurrence of type I antithrombin III deficiency (613118) and a heterozygous prothrombin 20210G-A mutation, who developed chronic thromboembolic pulmonary hypertension on the basis of total occlusion of the right pulmonary artery. Pulmonary vascular patency was restored successfully by surgical pulmonary thromboendarterectomy performed 24 weeks after the initial clinical presentation. </p><p>Segal et al. (2009) provided a metaanalysis of the predictive value of the prothrombin 20210G-A mutation for venous thromboembolism using a literature review of 10 relevant articles. Although heterozygosity for prothrombin 20210G-A in probands conferred a risk of 1.45, the confidence interval ranged from 0.96 to 2.2, suggesting that the mutation was not predictive of recurrent venous thromboembolism compared to those without the mutation. In addition, there was insufficient evidence regarding the predictive value of homozygosity for prothrombin 20210G-A in probands, and for the predictive value of being a mutation carrier in relatives of probands with the mutation. It remained unknown whether testing improved clinical outcomes. Segal et al. (2009) concluded that there is insufficient evidence to support the hypothesis that 20210G-A confers a significantly increased risk for venous thromboembolism in terms of genetic testing. </p><p>Ischemic Stroke</p><p>In a comprehensive metaanalysis of 19 case-control studies including 3,028 white adult patients, Casas et al. (2004) found a statistically significant association between ischemic stroke (601367) and the 20210G-A substitution (odds ratio of 1.44). </p><p>Budd-Chiari Syndrome</p><p>In a 37-year-old Caucasian male with polycythemia vera who had developed Budd-Chiari syndrome (BDCHS; 600880), Bucciarelli et al. (1998) identified heterozygosity for the 20210G-A substitution. His paternal grandmother had died at the age of 60 due to BDCHS, and his father, who was also heterozygous for the mutation, had had a myocardial infarction at age 55. Bucciarelli et al. (1998) excluded deficiencies of antithrombin, protein C, and protein S, as well as the presence of antiphospholipid syndrome and the factor V Leiden mutation. They suggested case-control studies to establish if carriers of the 20210G-A mutation have an increased risk of developing BDCHS. </p><p>Oner et al. (1999) described Budd-Chiari syndrome in a patient heterozygous for both the 20210G-A mutation of F2 and the factor V Leiden mutation; heterozygosity for the factor V Leiden mutation is a known susceptibility factor for BDCHS. Oner et al. (1999) referred to the 20210G-A mutation by the abbreviation PM, presumably for 'prothrombin mutation.' </p><p>Susceptibility to Recurrent Pregnancy Loss</p><p>Pihusch et al. (2001) studied clotting factors in 102 patients with 2 or more consecutive spontaneous abortions (RPRGL2; 614390) compared to 128 women without miscarriage and found that heterozygosity for the 20210G-A mutation of prothrombin was more common in patients with abortions in the first trimester (p = 0.027; odds ratio, 8.5). </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>.0010 DYSPROTHROMBINEMIA</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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F2, GLU300LYS
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<br />
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SNP: rs121918483,
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gnomAD: rs121918483,
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ClinVar: RCV002468929
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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 F2 variant is referred to as prothrombin Denver I.</p><p>Montgomery et al. (1980) described a form of dysprothrombinemia (see 613679) in a proband with a severe hemophilia-like bleeding disorder who was treated with weekly prophylactic prothrombin replacement. Lefkowitz et al. (2000) found that the patient was a compound heterozygote for 2 mutations in the F2 gene: glu300-to-lys (E300K) and glu309-to-lys (E309K; 176930.0011). Factor II activity was 5 units/dl and factor II antigen was 21 units/dl. The functional defect was apparently in the activation of zymogen to enzyme. </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>.0011 DYSPROTHROMBINEMIA</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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F2, GLU309LYS
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<br />
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SNP: rs121918484,
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gnomAD: rs121918484,
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ClinVar: RCV002468930
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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 F2 variant is referred to as prothrombin Denver II.</p><p>See (176930.0010) and Lefkowitz et al. (2000). </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>.0012 DYSPROTHROMBINEMIA</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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F2, ARG382HIS
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<br />
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SNP: rs121918485,
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gnomAD: rs121918485,
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ClinVar: RCV002468931
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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>Akhavan et al. (2000) described a homozygous arg382-to-his (R382H) substitution in the prothrombin gene of an Iranian girl with dysprothrombinemia (see 613679). The only symptoms were sporadic ecchymosis and 1 episode of buttock hematoma following a major trauma. A substitution in this residue had been identified in the compound heterozygous dysprothrombins Quick I (R382C; 176930.0004) and Corpus Christi. </p><p>Akhavan et al. (2002) investigated the functional properties of the R382H mutant protein. Their experiments showed that the R382H substitution drastically affected both the procoagulant and the anticoagulant functions of thrombin as well as its inhibition by heparin cofactor II (142360). The mild hemorrhagic phenotype may be explained by abnormalities that ultimately counterbalance each other. </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>.0013 DYSPROTHROMBINEMIA</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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F2, ASP552GLU
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<br />
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SNP: rs121918486,
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ClinVar: RCV002468932
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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 F2 variant is referred to as prothrombin Saint-Denis.</p><p>In a male newborn with dysprothrombinemia (see 613679), Rouy et al. (2006) identified a new prothrombin variant, with a point mutation at nucleotide 20029 resulting in an asp552-to-glu (D552E) substitution. Prothrombin levels were reduced in each of 3 assays. The substitution did not affect the rate of prothrombin conversion to thrombin, but altered thrombin activity. Amino acid 552 had been involved in the allosteric transition, which is induced by sodium binding to thrombin. This was the first known amino acid substitution at this site to result in dysprothrombinemia. The male newborn was referred because of fetal pulmonary hypertension and left ventricular failure, which resolved spontaneously. The father and mother, who were first cousins, had a slight decrease in prothrombin activity and normal levels of prothrombin antigen. No abnormal bleeding was observed in the proband at birth or in the first 30 months of his life, and both parents were asymptomatic. </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>.0014 HYPOPROTHROMBINEMIA</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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F2, TYR44CYS
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<br />
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SNP: rs1227147475,
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gnomAD: rs1227147475,
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ClinVar: RCV000852095, RCV001678590
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with congenital prothrombin deficiency (613679) and severe bleeding tendency, Poort et al. (1994) identified a homozygous A-to-G transition in exon 3 of the F2 gene, resulting in a tyr44-to-cys (Y44C) substitution. Laboratory studies showed factor II activity at about 2% and antigen levels at about 5%. Both parents were heterozygous for the mutation. Further family studies revealed complete cosegregation of the mutation with the prothrombin deficiency. Five homozygous brothers and sisters of the propositus were clinically affected with severe hemorrhages, including epistaxis, soft tissue, muscle, and joint bleedings in all, and severe menorrhagia in the 2 women. </p><p>Lancellotti and De Cristofaro (2009) noted that the Y44C mutation resulted from a 1305A-G change and affected the kringle-1 domain. The mutation was found in the family with hypoprothrombinemia reported by Van Creveld (1954). </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>.0015 THROMBOPHILIA DUE TO THROMBIN 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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F2, ARG596LEU
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<br />
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SNP: rs387907201,
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ClinVar: RCV000024607
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a Japanese family with recurrent thrombophilia due to thrombin defect (188050), Miyawaki et al. (2012) identified a heterozygous 1787G-T transversion in the F2 gene, resulting in an arg596-to-leu (R596L) substitution within the sodium-binding region of thrombin and also in 1 of the antithrombin-binding sites. The mutation was not found in unaffected family members or in 100 control individuals. In vitro ELISA studies showed that the mutant prothrombin did not form a complex with antithrombin (SERPINC1; 107300) even when heparin was added. A thrombin generation assay showed that the mutant prothrombin activity was lower than wildtype, but its inactivation in reconstituted plasma was exceedingly slow. Miyawaki et al. (2012) concluded that although the procoagulant activity of mutant prothrombin was somewhat impaired due to disruption of the sodium-binding site, the antithrombin:thrombin complex was considerably impaired due to disruption of that binding site, causing continued facilitation of coagulation. The findings indicated that R596L was a gain-of-function mutation resulting in the resistance to antithrombin, and conferring susceptibility to thrombosis. The mutant variant was termed 'prothrombin Yukuhashi.' </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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</h4>
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<span class="mim-text-font">
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Board et al. (1982); Degen et al. (1983); Henriksen and Owen (1987);
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Iwahana et al. (1992)
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</span>
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<br />
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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 class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 6/20/2012<br>Marla J. F. O'Neill - updated : 12/13/2011<br>Carol A. Bocchini - updated : 1/5/2011<br>Cassandra L. Kniffin - updated : 1/3/2011<br>Victor A. McKusick - updated : 9/28/2006<br>Victor A. McKusick - updated : 6/9/2006<br>Cassandra L. Kniffin - updated : 6/10/2005<br>Ada Hamosh - updated : 1/5/2004<br>Victor A. McKusick - updated : 10/16/2002<br>Victor A. McKusick - updated : 10/8/2002<br>Victor A. McKusick - updated : 11/7/2001<br>Victor A. McKusick - updated : 9/20/2001<br>Ada Hamosh - updated : 7/13/2001<br>Victor A. McKusick - updated : 2/26/2001<br>Victor A. McKusick - updated : 6/7/2000<br>Victor A. McKusick - updated : 2/24/2000<br>Victor A. McKusick - updated : 2/1/2000<br>Victor A. McKusick - updated : 1/10/2000<br>George E. Tiller - updated : 11/16/1999<br>Victor A. McKusick - updated : 7/13/1999<br>Ada Hamosh - updated : 5/18/1999<br>Victor A. McKusick - updated : 3/25/1999<br>Victor A. McKusick - updated : 9/29/1998<br>Victor A. McKusick - updated : 8/21/1998<br>Victor A. McKusick - updated : 6/25/1998<br>Victor A. McKusick - updated : 6/10/1998
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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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<br />
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Victor A. McKusick : 6/2/1986
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carol : 02/22/2022<br>carol : 06/04/2019<br>alopez : 05/31/2018<br>alopez : 09/07/2016<br>carol : 08/30/2016<br>carol : 01/29/2015<br>carol : 6/20/2012<br>ckniffin : 6/20/2012<br>carol : 3/1/2012<br>carol : 2/28/2012<br>alopez : 12/13/2011<br>carol : 7/19/2011<br>carol : 4/8/2011<br>carol : 4/7/2011<br>carol : 2/11/2011<br>terry : 1/5/2011<br>carol : 1/5/2011<br>carol : 1/5/2011<br>carol : 1/4/2011<br>carol : 1/4/2011<br>ckniffin : 1/3/2011<br>carol : 11/18/2009<br>ckniffin : 11/11/2009<br>alopez : 6/16/2009<br>terry : 5/4/2009<br>carol : 10/8/2008<br>carol : 9/29/2008<br>carol : 10/3/2006<br>terry : 9/28/2006<br>alopez : 7/5/2006<br>terry : 6/9/2006<br>carol : 6/13/2005<br>ckniffin : 6/10/2005<br>carol : 3/17/2004<br>cwells : 1/7/2004<br>terry : 1/5/2004<br>tkritzer : 11/19/2002<br>tkritzer : 11/1/2002<br>tkritzer : 10/22/2002<br>terry : 10/16/2002<br>carol : 10/16/2002<br>tkritzer : 10/14/2002<br>terry : 10/8/2002<br>carol : 11/26/2001<br>mcapotos : 11/16/2001<br>mcapotos : 11/16/2001<br>terry : 11/7/2001<br>carol : 10/12/2001<br>mcapotos : 9/27/2001<br>mcapotos : 9/21/2001<br>terry : 9/20/2001<br>alopez : 8/2/2001<br>alopez : 7/16/2001<br>terry : 7/13/2001<br>mcapotos : 3/6/2001<br>mcapotos : 3/2/2001<br>terry : 2/26/2001<br>mcapotos : 2/13/2001<br>carol : 7/6/2000<br>mcapotos : 6/28/2000<br>mcapotos : 6/23/2000<br>terry : 6/7/2000<br>alopez : 3/22/2000<br>alopez : 3/22/2000<br>alopez : 3/21/2000<br>mcapotos : 3/17/2000<br>mcapotos : 3/1/2000<br>terry : 2/24/2000<br>mcapotos : 2/14/2000<br>mcapotos : 2/9/2000<br>terry : 2/1/2000<br>mcapotos : 1/20/2000<br>mcapotos : 1/19/2000<br>terry : 1/10/2000<br>alopez : 11/16/1999<br>carol : 7/23/1999<br>jlewis : 7/21/1999<br>terry : 7/13/1999<br>alopez : 5/24/1999<br>terry : 5/18/1999<br>mgross : 4/2/1999<br>mgross : 3/31/1999<br>terry : 3/25/1999<br>terry : 10/1/1998<br>carol : 9/30/1998<br>terry : 9/29/1998<br>carol : 8/24/1998<br>terry : 8/21/1998<br>dholmes : 7/22/1998<br>alopez : 6/26/1998<br>terry : 6/25/1998<br>terry : 6/11/1998<br>dholmes : 6/10/1998<br>terry : 8/8/1997<br>carol : 6/20/1997<br>mark : 6/14/1997<br>mark : 6/25/1996<br>mimadm : 2/25/1995<br>davew : 8/19/1994<br>terry : 7/15/1994<br>warfield : 3/11/1994<br>carol : 7/13/1993<br>carol : 1/21/1993
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