3140 lines
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3140 lines
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- *604720 - TRANSFERRIN RECEPTOR 2; TFR2
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*604720</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/604720">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000106327;t=ENST00000223051" 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=7036" 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=604720" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000106327;t=ENST00000223051" 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_001206855,NM_003227" 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_003227" 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=604720" 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=05282&isoform_id=05282_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/TFR2" 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/5596370,7020498,10433314,20140912,33589848,94717647,119596912,119596913,119596914,119596915,119596916,148744329,152013009,332309171" 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/Q9UP52" 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=7036" 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=ENSG00000106327;t=ENST00000223051" 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=TFR2" 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=TFR2" 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+7036" 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/TFR2" 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:7036" 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/7036" 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=chr7&hgg_gene=ENST00000223051.8&hgg_start=100620420&hgg_end=100641552&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:11762" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/tfr2" 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=604720[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=604720[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/ENSG00000106327" 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=TFR2" 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=TFR2" 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=TFR2" 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=TFR2&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/PA36477" 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:11762" 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:1354956" 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/TFR2#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:1354956" 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/7036/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=7036" 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-041220-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7036" 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=TFR2&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> 719974003<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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604720
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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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TRANSFERRIN RECEPTOR 2; TFR2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TFR2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TFR2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/7/510?start=-3&limit=10&highlight=510">7q22.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:100620420-100641552&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'})">7:100,620,420-100,641,552</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/7/510?start=-3&limit=10&highlight=510">
|
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7q22.1
|
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</a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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Hemochromatosis, type 3
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/604250"> 604250 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/604720" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/604720" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<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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</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="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
|
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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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<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
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<div>
|
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<a id="cloning" class="mim-anchor"></a>
|
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
|
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</span>
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</h4>
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</div>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>While attempting to isolate genes encoding new transcriptional factors from a TF-1 (erythroid leukemia) cell cDNA library, <a href="#6" class="mim-tip-reference" title="Kawabata, H., Yang, R., Hirama, T., Vuong, P. T., Kawano, S., Gombart, A. F., Koeffler, H. P. <strong>Molecular cloning of transferrin receptor 2: a new member of the transferrin receptor-like family.</strong> J. Biol. Chem. 274: 20826-20832, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10409623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10409623</a>] [<a href="https://doi.org/10.1074/jbc.274.30.20826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10409623">Kawabata et al. (1999)</a> cloned an 831-bp human cDNA fragment that had significant amino acid homology to the middle portion of the classic transferrin receptor protein (TFRC; <a href="/entry/190010">190010</a>). Using 5-prime/3-prime RACE, they cloned a full-length, 2.9-kb cDNA, which they designated TFR2. They identified 2 transcripts: a 2.9-kb transcript, called alpha, and an approximately 2.5-kb transcript, called beta, which was cloned from an HL60 (myeloid leukemia) cell cDNA library. The alpha form predicts an 801-amino acid type II membrane protein that shares 45% identity and 66% similarity in its extracellular domain with TFRC. The beta form, which may be an alternative product of splicing or promoter usage, lacks the amino-terminal portion of TFR2-alpha, including the putative transmembrane domain. Northern blot analysis showed that the alpha form is predominantly expressed in the liver and also in the K562 erythromegakaryocytic cell line; no expression of the beta form was found. By RT-PCR analysis, TFR2-alpha was expressed in the liver, spleen, lung, muscle, prostate, and peripheral blood mononuclear cells, whereas expression of TFR-beta was found in all tissues tested. Expression of human TFR2 conferred binding of holotransferrin and uptake of transferrin-bound iron to a Chinese hamster ovary cell line lacking endogenous TFRC. <a href="#6" class="mim-tip-reference" title="Kawabata, H., Yang, R., Hirama, T., Vuong, P. T., Kawano, S., Gombart, A. F., Koeffler, H. P. <strong>Molecular cloning of transferrin receptor 2: a new member of the transferrin receptor-like family.</strong> J. Biol. Chem. 274: 20826-20832, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10409623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10409623</a>] [<a href="https://doi.org/10.1074/jbc.274.30.20826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10409623">Kawabata et al. (1999)</a> concluded that TFR2-alpha may be a second transferrin receptor that can mediate cellular iron transport. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10409623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The majority of hepatic iron uptake under normal circumstances is transferrin-mediated. However, expression of TFRC in hepatocytes, as in other nonreticuloendothelial cell types, is downregulated in response to increased intracellular iron. As a consequence, TFRC expression in liver is undetectable in hereditary hemochromatosis (<a href="/entry/235200">235200</a>) patients with hepatic iron loading. Nonetheless, hepatic iron loading in hemochromatosis patients is progressive. <a href="#4" class="mim-tip-reference" title="Fleming, R. E., Migas, M. C., Holden, C. C., Waheed, A., Britton, R. S., Tomatsu, S., Bacon, B. R., Sly, W. S. <strong>Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis.</strong> Proc. Nat. Acad. Sci. 97: 2214-2219, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10681454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10681454</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10681454[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.040548097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10681454">Fleming et al. (2000)</a> provided support for a mechanism that involves the uptake of transferrin-bound iron by TFR2. By screening a murine EST database for Tfrc sequences, they identified a cDNA encoding a protein homologous to murine Tfrc. They characterized the murine TFR2 ortholog and compared expression of murine Tfrc and Tfr2 in normal mice, mice with iron deficiency, and mice with iron overload. Unlike Tfrc, the Tfr2 transcript was highly expressed in hepatocytes, was not regulated by tissue iron status, and was not downregulated in a murine model of hereditary hemochromatosis. From these observations, <a href="#4" class="mim-tip-reference" title="Fleming, R. E., Migas, M. C., Holden, C. C., Waheed, A., Britton, R. S., Tomatsu, S., Bacon, B. R., Sly, W. S. <strong>Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis.</strong> Proc. Nat. Acad. Sci. 97: 2214-2219, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10681454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10681454</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10681454[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.040548097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10681454">Fleming et al. (2000)</a> proposed that TFR2 continues to mediate uptake of transferrin-bound iron by the liver after TFRC is downregulated by iron overload, and thus may explain increased susceptibility of the liver to iron loading in hereditary hemochromatosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10681454" 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="#6" class="mim-tip-reference" title="Kawabata, H., Yang, R., Hirama, T., Vuong, P. T., Kawano, S., Gombart, A. F., Koeffler, H. P. <strong>Molecular cloning of transferrin receptor 2: a new member of the transferrin receptor-like family.</strong> J. Biol. Chem. 274: 20826-20832, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10409623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10409623</a>] [<a href="https://doi.org/10.1074/jbc.274.30.20826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10409623">Kawabata et al. (1999)</a> determined the genomic structure of the TFR2 gene. The alpha transcript contains 18 exons. The beta transcript lacks exons 1 through 3 and has an additional 142 bases at the 5-prime end of exon 4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10409623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By radiation hybrid analysis, <a href="#6" class="mim-tip-reference" title="Kawabata, H., Yang, R., Hirama, T., Vuong, P. T., Kawano, S., Gombart, A. F., Koeffler, H. P. <strong>Molecular cloning of transferrin receptor 2: a new member of the transferrin receptor-like family.</strong> J. Biol. Chem. 274: 20826-20832, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10409623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10409623</a>] [<a href="https://doi.org/10.1074/jbc.274.30.20826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10409623">Kawabata et al. (1999)</a> mapped the TFR2 gene to chromosome 7q22. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10409623" 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="#1" class="mim-tip-reference" title="Camaschella, C., Roetto, A., Cali, A., De Gobbi, M., Garozzo, G., Carella, M., Majorano, N., Totaro, A., Gasparini, P. <strong>The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22.</strong> Nature Genet. 25: 14-15, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802645</a>] [<a href="https://doi.org/10.1038/75534" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10802645">Camaschella et al. (2000)</a> identified a premature termination mutation at codon 250 in the TFR2 gene in homozygosity in a Sicilian family segregating hemochromatosis type 3 (HFE3; <a href="/entry/604250">604250</a>). The Y250X mutation (<a href="#0001">604720.0001</a>) identified by <a href="#1" class="mim-tip-reference" title="Camaschella, C., Roetto, A., Cali, A., De Gobbi, M., Garozzo, G., Carella, M., Majorano, N., Totaro, A., Gasparini, P. <strong>The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22.</strong> Nature Genet. 25: 14-15, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802645</a>] [<a href="https://doi.org/10.1038/75534" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10802645">Camaschella et al. (2000)</a> is located in a region shared by both the alpha and beta transcripts of TFR2. A phenotype of iron overload associated with the absence of the functional gene suggested TFR2 is more likely involved in iron regulation rather than iron uptake. Although TFR2 is highly expressed in an erythroid cell line, none of the HFE3 patients that they studied showed erythrocyte abnormalities. Rather, the patients tolerated long-term phlebotomies without developing anemia. Thus, <a href="#1" class="mim-tip-reference" title="Camaschella, C., Roetto, A., Cali, A., De Gobbi, M., Garozzo, G., Carella, M., Majorano, N., Totaro, A., Gasparini, P. <strong>The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22.</strong> Nature Genet. 25: 14-15, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802645</a>] [<a href="https://doi.org/10.1038/75534" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10802645">Camaschella et al. (2000)</a> concluded that TFR2, in contrast to TFRC, is not essential during erythroid maturation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10802645" 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="#2" class="mim-tip-reference" title="Feder, J. N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D. A., Basava, A., Dormishian, F., Domingo, R., Jr., Ellis, M. C., Fullan, A., Hinton, L. M., Jones, N. L., and 21 others. <strong>A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.</strong> Nature Genet. 13: 399-408, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696333</a>] [<a href="https://doi.org/10.1038/ng0896-399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696333">Feder et al. (1996)</a> found that about 15% of hereditary hemochromatosis patients of northern European descent do not carry the C282Y mutation of the HFE gene (<a href="/entry/613609#0001">613609.0001</a>). <a href="#7" class="mim-tip-reference" title="Mattman, A., Huntsman, D., Lockitch, G., Langlois, S., Buskard, N., Ralston, D., Butterfield, Y., Rodrigues, P., Jones, S., Porto, G., Marra, M., De Sousa, M., Vatcher, G. <strong>Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation.</strong> Blood 100: 1075-1077, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12130528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12130528</a>] [<a href="https://doi.org/10.1182/blood-2002-01-0133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12130528">Mattman et al. (2002)</a> studied a group of non-C282Y hemochromatosis patients and identified several sequence variants, including a homozygous missense mutation in exon 17 of the TFR2 gene, which resulted in a gln690-to-pro amino acid change (<a href="#0005">604720.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8696333+12130528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Hofmann, W.-K., Tong, X.-J., Ajioka, R. S., Kushner, J. P., Koeffler, H. P. <strong>Mutation analysis of transferrin-receptor 2 in patients with atypical hemochromatosis. (Letter)</strong> Blood 100: 1099-1100, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12150153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12150153</a>] [<a href="https://doi.org/10.1182/blood-2002-04-1077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12150153">Hofmann et al. (2002)</a> performed mutation analysis of the TFR2 gene in patients with atypical hemochromatosis. They also questioned whether differences in penetrance of the HFE C282Y mutation (<a href="/entry/613609#0001">613609.0001</a>) were associated with mutations in the TFR2 gene. They studied sib pairs homozygous for cys282-to-tyr with a discordant phenotype. The most common discordance between homozygous sibs was in serum transferrin concentration. Many of these patients, however, also exhibited significant differences in liver fibrosis and liver enzyme levels. They also studied individuals who were not homozygous for C282Y with evidence of iron excess, and other atypical groups. In a pair of brothers homozygous for the C282Y mutation, they found an arg455-to-gln mutation in TFR2 (<a href="#0004">604720.0004</a>) only in the brother with liver fibrosis, suggesting that TFR2 functions as a modifier for penetrance of the hemochromatosis phenotype when present with homozygosity for C282Y. Unlike TFR1 expression, TFR2 expression is not downregulated in the liver of iron-loaded mice (<a href="#4" class="mim-tip-reference" title="Fleming, R. E., Migas, M. C., Holden, C. C., Waheed, A., Britton, R. S., Tomatsu, S., Bacon, B. R., Sly, W. S. <strong>Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis.</strong> Proc. Nat. Acad. Sci. 97: 2214-2219, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10681454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10681454</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10681454[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.040548097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10681454">Fleming et al., 2000</a>). The screening for mutations in all 18 exons indicated that mutations of the TFR2 gene are rare. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10681454+12150153" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Wallace, D. F., Subramaniam, V. N. <strong>The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data.</strong> Genet. Med. 18: 618-626, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26633544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26633544</a>] [<a href="https://doi.org/10.1038/gim.2015.140" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26633544">Wallace and Subramaniam (2016)</a> reviewed 161 variants previously associated with any form of hereditary hemochromatosis and found that 43 were represented among next-generation sequence public databases including ESP, 1000 Genomes Project, and ExAC. The frequency of the C282Y mutation in HFE (<a href="/entry/613609#0001">613609.0001</a>) matched previous estimates from similar populations. Of the non-HFE forms of iron overload, TFR2-, HFE2 (<a href="/entry/608374">608374</a>)-, and HAMP (<a href="/entry/606464">606464</a>)-related forms were extremely rare, with pathogenic allele frequencies in the range of 0.00007 to 0.0005. However, SLC40A1 (<a href="/entry/604653">604653</a>) variants were identified in several populations (pathogenic allele frequency 0.0004), being most prevalent among Africans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26633544" 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>To characterize the role of TFR2 in iron homeostasis, <a href="#3" class="mim-tip-reference" title="Fleming, R. E., Ahmann, J. R., Migas, M. C., Waheed, A., Koeffler, H. P., Kawabata, H., Britton, R. S., Bacon, B. R., Sly, W. S. <strong>Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis.</strong> Proc. Nat. Acad. Sci. 99: 10653-10658, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12134060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12134060</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12134060[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.162360699" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12134060">Fleming et al. (2002)</a> generated a premature stop codon (Y245X), which was introduced by targeted mutagenesis in the murine Tfr2 coding sequence. Codon 245 is the mouse ortholog of codon 250, which is involved in the C250Y mutation (<a href="#0001">604720.0001</a>) of TFR2 in human hemochromatosis, and is located in a region that is conserved between the mouse and human genomes. <a href="#3" class="mim-tip-reference" title="Fleming, R. E., Ahmann, J. R., Migas, M. C., Waheed, A., Koeffler, H. P., Kawabata, H., Britton, R. S., Bacon, B. R., Sly, W. S. <strong>Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis.</strong> Proc. Nat. Acad. Sci. 99: 10653-10658, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12134060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12134060</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12134060[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.162360699" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12134060">Fleming et al. (2002)</a> observed that by 4 weeks of age, mice homozygous for the Y245X mutation developed periportal hepatic iron loading, splenic iron sparing, and elevated serum transferrin saturations. Thus, the mutant mice seemed to provide a faithful model for the abnormalities in iron homeostasis observed in patients with loss of TFR2. Heterozygous mice did not differ in any measured parameter from wildtype mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12134060" 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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<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>5 Selected Examples</a>):</strong>
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<a href="/allelicVariants/604720" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=604720[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 HEMOCHROMATOSIS, TYPE 3</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> rs80338880 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338880;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/rs80338880?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=rs80338880" 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=rs80338880" 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=RCV000005711" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005711" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005711</a>
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<p>In 2 families from Sicily who met diagnostic criteria for hemochromatosis (HFE3; <a href="/entry/604250">604250</a>) but were not linked to the HFE locus (<a href="/entry/235200">235200</a>), one of which was consanguineous, <a href="#1" class="mim-tip-reference" title="Camaschella, C., Roetto, A., Cali, A., De Gobbi, M., Garozzo, G., Carella, M., Majorano, N., Totaro, A., Gasparini, P. <strong>The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22.</strong> Nature Genet. 25: 14-15, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802645</a>] [<a href="https://doi.org/10.1038/75534" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10802645">Camaschella et al. (2000)</a> identified a C-to-G transversion in exon 6 at position 750 of the TFR2 cDNA sequence, resulting in a tyrosine (TAC)-to-stop (TAG) substitution at residue 250 (Y250X). This substitution created a MaeI site. All affected members of the consanguineous family were homozygous for Y250X, whereas obligate carriers were heterozygous. One patient in the nonconsanguineous family was homozygous for this mutation. <a href="#1" class="mim-tip-reference" title="Camaschella, C., Roetto, A., Cali, A., De Gobbi, M., Garozzo, G., Carella, M., Majorano, N., Totaro, A., Gasparini, P. <strong>The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22.</strong> Nature Genet. 25: 14-15, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802645</a>] [<a href="https://doi.org/10.1038/75534" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10802645">Camaschella et al. (2000)</a> did not find the Y250X mutation in 100 normal chromosomes or in 12 hemochromatosis patients who did not have mutations in HFE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10802645" 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> rs80338877 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338877;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/rs80338877?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=rs80338877" 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=rs80338877" 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=RCV000005712 OR RCV001381389" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005712, RCV001381389" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005712...</a>
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<p>In all affected members of a large inbred family in Campania in southern Italy segregating hemochromatosis (HFE3; <a href="/entry/604250">604250</a>), <a href="#8" class="mim-tip-reference" title="Roetto, A., Totaro, A., Piperno, A., Piga, A., Longo, F., Garozzo, G., Cali, A., De Gobbi, M., Gasparini, P., Camaschella, C. <strong>New mutations inactivating transferrin receptor 2 in hemochromatosis type 3.</strong> Blood 97: 2555-2560, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11313241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11313241</a>] [<a href="https://doi.org/10.1182/blood.v97.9.2555" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11313241">Roetto et al. (2001)</a> found a 1-bp insertion of a cytosine residue in homozygous state in exon 2 in a polyC tract (84-88 insC). The mutation resulted in a frameshift followed by a premature stop codon, a glu60-to-ter (E60X) substitution. Because of consanguinity, a pseudodominant pedigree pattern was observed in an affected father and his 3 affected children in one branch of the family. Heterozygosity was not associated with iron overload, even in individuals also heterozygous for H63D (<a href="/entry/613609#0002">613609.0002</a>) at the HFE locus or for the beta-thalassemia trait. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11313241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 HEMOCHROMATOSIS, TYPE 3</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> rs80338879 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338879;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/rs80338879?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=rs80338879" 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=rs80338879" 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=RCV000005713" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005713" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005713</a>
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<p>In a family in which the proband had severe hemochromatosis (HFE3; <a href="/entry/604250">604250</a>), <a href="#8" class="mim-tip-reference" title="Roetto, A., Totaro, A., Piperno, A., Piga, A., Longo, F., Garozzo, G., Cali, A., De Gobbi, M., Gasparini, P., Camaschella, C. <strong>New mutations inactivating transferrin receptor 2 in hemochromatosis type 3.</strong> Blood 97: 2555-2560, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11313241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11313241</a>] [<a href="https://doi.org/10.1182/blood.v97.9.2555" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11313241">Roetto et al. (2001)</a> found homozygosity for a T-to-A transversion (515T-A) in exon 4 of TFR2 cDNA, resulting in a met172-to-lys (M172K) substitution of the protein. The proband had cirrhosis, hypogonadism, and cardiac disease. He had inherited beta-thalassemia in heterozygous state from his mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11313241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 HEMOCHROMATOSIS, TYPE 1, MODIFIER OF</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> rs41303501 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs41303501;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/rs41303501?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=rs41303501" 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=rs41303501" 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=RCV000005714 OR RCV000020537 OR RCV000168108 OR RCV001081144 OR RCV003914812" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005714, RCV000020537, RCV000168108, RCV001081144, RCV003914812" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005714...</a>
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<p><a href="#5" class="mim-tip-reference" title="Hofmann, W.-K., Tong, X.-J., Ajioka, R. S., Kushner, J. P., Koeffler, H. P. <strong>Mutation analysis of transferrin-receptor 2 in patients with atypical hemochromatosis. (Letter)</strong> Blood 100: 1099-1100, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12150153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12150153</a>] [<a href="https://doi.org/10.1182/blood-2002-04-1077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12150153">Hofmann et al. (2002)</a> studied 2 brothers who were homozygous for the common hemochromatosis-causing mutation of the HFE gene, cys282 to tyr (<a href="/entry/613609#0001">613609.0001</a>). Direct nucleotide sequencing found a G-to-A transversion at nucleotide 1391, resulting in an arg455-to-gln (R455Q) amino acid change in the TFR2 gene. The R455Q mutation was present in only 1 of the brothers homozygous for C282Y; that brother had evidence of liver fibrosis, whereas the other brother did not. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12150153" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 HEMOCHROMATOSIS, TYPE 3</strong>
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TFR2, GLN690PRO
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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> rs80338889 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338889;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/rs80338889?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=rs80338889" 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=rs80338889" 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=RCV000005715" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005715" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005715</a>
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<p>In a Portuguese man with severe hemochromatosis (HFE3; <a href="/entry/604250">604250</a>) and in 2 family members, <a href="#7" class="mim-tip-reference" title="Mattman, A., Huntsman, D., Lockitch, G., Langlois, S., Buskard, N., Ralston, D., Butterfield, Y., Rodrigues, P., Jones, S., Porto, G., Marra, M., De Sousa, M., Vatcher, G. <strong>Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation.</strong> Blood 100: 1075-1077, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12130528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12130528</a>] [<a href="https://doi.org/10.1182/blood-2002-01-0133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12130528">Mattman et al. (2002)</a> found a gln690-to-pro (Q690P) mutation in the TFR2 gene. The patient presented at 29 years of age with fatigue, hypogonadotropic hypogonadism, hyperpigmentation, mild elevation of liver transaminases, and idiopathic thrombocytopenic purpura. He had markedly elevated serum iron indices and had had more than 12 g of iron removed via phlebotomy in the previous 4 years. Additional hematologic abnormalities included mild normocytic anemia and lymphopenia. He was heterozygous for the H63D mutation in the HFE gene (<a href="/entry/613609#0002">613609.0002</a>). <a href="#7" class="mim-tip-reference" title="Mattman, A., Huntsman, D., Lockitch, G., Langlois, S., Buskard, N., Ralston, D., Butterfield, Y., Rodrigues, P., Jones, S., Porto, G., Marra, M., De Sousa, M., Vatcher, G. <strong>Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation.</strong> Blood 100: 1075-1077, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12130528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12130528</a>] [<a href="https://doi.org/10.1182/blood-2002-01-0133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12130528">Mattman et al. (2002)</a> stated that this patient was the only one of 89 non-C282Y hereditary chromatosis patients of predominately mixed European descent in whom mutation of the TFR2 gene had been found. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12130528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Camaschella2000" class="mim-anchor"></a>
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Camaschella, C., Roetto, A., Cali, A., De Gobbi, M., Garozzo, G., Carella, M., Majorano, N., Totaro, A., Gasparini, P.
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<strong>The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22.</strong>
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Nature Genet. 25: 14-15, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802645</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10802645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/75534" target="_blank">Full Text</a>]
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Feder, J. N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D. A., Basava, A., Dormishian, F., Domingo, R., Jr., Ellis, M. C., Fullan, A., Hinton, L. M., Jones, N. L., and 21 others.
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<strong>A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.</strong>
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Nature Genet. 13: 399-408, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696333</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8696333" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng0896-399" target="_blank">Full Text</a>]
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Fleming, R. E., Ahmann, J. R., Migas, M. C., Waheed, A., Koeffler, H. P., Kawabata, H., Britton, R. S., Bacon, B. R., Sly, W. S.
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<strong>Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis.</strong>
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Proc. Nat. Acad. Sci. 99: 10653-10658, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12134060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12134060</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12134060[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12134060" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.162360699" target="_blank">Full Text</a>]
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Fleming, R. E., Migas, M. C., Holden, C. C., Waheed, A., Britton, R. S., Tomatsu, S., Bacon, B. R., Sly, W. S.
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<strong>Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis.</strong>
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Proc. Nat. Acad. Sci. 97: 2214-2219, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10681454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10681454</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10681454[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10681454" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.040548097" target="_blank">Full Text</a>]
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Hofmann, W.-K., Tong, X.-J., Ajioka, R. S., Kushner, J. P., Koeffler, H. P.
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<strong>Mutation analysis of transferrin-receptor 2 in patients with atypical hemochromatosis. (Letter)</strong>
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Blood 100: 1099-1100, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12150153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12150153</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12150153" 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-2002-04-1077" target="_blank">Full Text</a>]
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Kawabata, H., Yang, R., Hirama, T., Vuong, P. T., Kawano, S., Gombart, A. F., Koeffler, H. P.
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<strong>Molecular cloning of transferrin receptor 2: a new member of the transferrin receptor-like family.</strong>
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J. Biol. Chem. 274: 20826-20832, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10409623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10409623</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10409623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.274.30.20826" target="_blank">Full Text</a>]
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Mattman, A., Huntsman, D., Lockitch, G., Langlois, S., Buskard, N., Ralston, D., Butterfield, Y., Rodrigues, P., Jones, S., Porto, G., Marra, M., De Sousa, M., Vatcher, G.
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<strong>Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation.</strong>
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Blood 100: 1075-1077, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12130528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12130528</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12130528" 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-2002-01-0133" target="_blank">Full Text</a>]
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Roetto, A., Totaro, A., Piperno, A., Piga, A., Longo, F., Garozzo, G., Cali, A., De Gobbi, M., Gasparini, P., Camaschella, C.
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<strong>New mutations inactivating transferrin receptor 2 in hemochromatosis type 3.</strong>
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Blood 97: 2555-2560, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11313241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11313241</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11313241" 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.v97.9.2555" target="_blank">Full Text</a>]
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Wallace, D. F., Subramaniam, V. N.
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<strong>The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data.</strong>
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Genet. Med. 18: 618-626, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26633544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26633544</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26633544" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/gim.2015.140" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Ada Hamosh - updated : 10/23/2018
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Victor A. McKusick - updated : 3/6/2003<br>Victor A. McKusick - updated : 3/4/2003<br>Victor A. McKusick - updated : 9/27/2002<br>Victor A. McKusick - updated : 7/17/2001<br>Ada Hamosh - updated : 4/27/2000<br>Wilson H. Y. Lo - updated : 4/4/2000
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 3/23/2000
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 10/24/2018
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 10/23/2018<br>alopez : 03/01/2018<br>carol : 10/21/2010<br>carol : 3/17/2006<br>terry : 9/8/2003<br>cwells : 3/6/2003<br>terry : 3/4/2003<br>cwells : 10/1/2002<br>carol : 9/27/2002<br>mcapotos : 8/7/2001<br>mcapotos : 7/26/2001<br>terry : 7/17/2001<br>alopez : 7/9/2001<br>carol : 7/6/2000<br>alopez : 4/28/2000<br>terry : 4/27/2000<br>carol : 4/6/2000<br>carol : 4/4/2000<br>mgross : 3/24/2000<br>mgross : 3/23/2000
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 604720
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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TRANSFERRIN RECEPTOR 2; TFR2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TFR2</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 719974003;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 7q22.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:100,620,420-100,641,552 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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7q22.1
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</span>
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</td>
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<td>
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<span class="mim-font">
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Hemochromatosis, type 3
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</span>
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</td>
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<td>
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<span class="mim-font">
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604250
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>While attempting to isolate genes encoding new transcriptional factors from a TF-1 (erythroid leukemia) cell cDNA library, Kawabata et al. (1999) cloned an 831-bp human cDNA fragment that had significant amino acid homology to the middle portion of the classic transferrin receptor protein (TFRC; 190010). Using 5-prime/3-prime RACE, they cloned a full-length, 2.9-kb cDNA, which they designated TFR2. They identified 2 transcripts: a 2.9-kb transcript, called alpha, and an approximately 2.5-kb transcript, called beta, which was cloned from an HL60 (myeloid leukemia) cell cDNA library. The alpha form predicts an 801-amino acid type II membrane protein that shares 45% identity and 66% similarity in its extracellular domain with TFRC. The beta form, which may be an alternative product of splicing or promoter usage, lacks the amino-terminal portion of TFR2-alpha, including the putative transmembrane domain. Northern blot analysis showed that the alpha form is predominantly expressed in the liver and also in the K562 erythromegakaryocytic cell line; no expression of the beta form was found. By RT-PCR analysis, TFR2-alpha was expressed in the liver, spleen, lung, muscle, prostate, and peripheral blood mononuclear cells, whereas expression of TFR-beta was found in all tissues tested. Expression of human TFR2 conferred binding of holotransferrin and uptake of transferrin-bound iron to a Chinese hamster ovary cell line lacking endogenous TFRC. Kawabata et al. (1999) concluded that TFR2-alpha may be a second transferrin receptor that can mediate cellular iron transport. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The majority of hepatic iron uptake under normal circumstances is transferrin-mediated. However, expression of TFRC in hepatocytes, as in other nonreticuloendothelial cell types, is downregulated in response to increased intracellular iron. As a consequence, TFRC expression in liver is undetectable in hereditary hemochromatosis (235200) patients with hepatic iron loading. Nonetheless, hepatic iron loading in hemochromatosis patients is progressive. Fleming et al. (2000) provided support for a mechanism that involves the uptake of transferrin-bound iron by TFR2. By screening a murine EST database for Tfrc sequences, they identified a cDNA encoding a protein homologous to murine Tfrc. They characterized the murine TFR2 ortholog and compared expression of murine Tfrc and Tfr2 in normal mice, mice with iron deficiency, and mice with iron overload. Unlike Tfrc, the Tfr2 transcript was highly expressed in hepatocytes, was not regulated by tissue iron status, and was not downregulated in a murine model of hereditary hemochromatosis. From these observations, Fleming et al. (2000) proposed that TFR2 continues to mediate uptake of transferrin-bound iron by the liver after TFRC is downregulated by iron overload, and thus may explain increased susceptibility of the liver to iron loading in hereditary hemochromatosis. </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>Kawabata et al. (1999) determined the genomic structure of the TFR2 gene. The alpha transcript contains 18 exons. The beta transcript lacks exons 1 through 3 and has an additional 142 bases at the 5-prime end of exon 4. </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">
|
|
<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
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<p>By radiation hybrid analysis, Kawabata et al. (1999) mapped the TFR2 gene to chromosome 7q22. </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>Camaschella et al. (2000) identified a premature termination mutation at codon 250 in the TFR2 gene in homozygosity in a Sicilian family segregating hemochromatosis type 3 (HFE3; 604250). The Y250X mutation (604720.0001) identified by Camaschella et al. (2000) is located in a region shared by both the alpha and beta transcripts of TFR2. A phenotype of iron overload associated with the absence of the functional gene suggested TFR2 is more likely involved in iron regulation rather than iron uptake. Although TFR2 is highly expressed in an erythroid cell line, none of the HFE3 patients that they studied showed erythrocyte abnormalities. Rather, the patients tolerated long-term phlebotomies without developing anemia. Thus, Camaschella et al. (2000) concluded that TFR2, in contrast to TFRC, is not essential during erythroid maturation. </p><p>Feder et al. (1996) found that about 15% of hereditary hemochromatosis patients of northern European descent do not carry the C282Y mutation of the HFE gene (613609.0001). Mattman et al. (2002) studied a group of non-C282Y hemochromatosis patients and identified several sequence variants, including a homozygous missense mutation in exon 17 of the TFR2 gene, which resulted in a gln690-to-pro amino acid change (604720.0005). </p><p>Hofmann et al. (2002) performed mutation analysis of the TFR2 gene in patients with atypical hemochromatosis. They also questioned whether differences in penetrance of the HFE C282Y mutation (613609.0001) were associated with mutations in the TFR2 gene. They studied sib pairs homozygous for cys282-to-tyr with a discordant phenotype. The most common discordance between homozygous sibs was in serum transferrin concentration. Many of these patients, however, also exhibited significant differences in liver fibrosis and liver enzyme levels. They also studied individuals who were not homozygous for C282Y with evidence of iron excess, and other atypical groups. In a pair of brothers homozygous for the C282Y mutation, they found an arg455-to-gln mutation in TFR2 (604720.0004) only in the brother with liver fibrosis, suggesting that TFR2 functions as a modifier for penetrance of the hemochromatosis phenotype when present with homozygosity for C282Y. Unlike TFR1 expression, TFR2 expression is not downregulated in the liver of iron-loaded mice (Fleming et al., 2000). The screening for mutations in all 18 exons indicated that mutations of the TFR2 gene are rare. </p><p>Wallace and Subramaniam (2016) reviewed 161 variants previously associated with any form of hereditary hemochromatosis and found that 43 were represented among next-generation sequence public databases including ESP, 1000 Genomes Project, and ExAC. The frequency of the C282Y mutation in HFE (613609.0001) matched previous estimates from similar populations. Of the non-HFE forms of iron overload, TFR2-, HFE2 (608374)-, and HAMP (606464)-related forms were extremely rare, with pathogenic allele frequencies in the range of 0.00007 to 0.0005. However, SLC40A1 (604653) variants were identified in several populations (pathogenic allele frequency 0.0004), being most prevalent among Africans. </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>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>To characterize the role of TFR2 in iron homeostasis, Fleming et al. (2002) generated a premature stop codon (Y245X), which was introduced by targeted mutagenesis in the murine Tfr2 coding sequence. Codon 245 is the mouse ortholog of codon 250, which is involved in the C250Y mutation (604720.0001) of TFR2 in human hemochromatosis, and is located in a region that is conserved between the mouse and human genomes. Fleming et al. (2002) observed that by 4 weeks of age, mice homozygous for the Y245X mutation developed periportal hepatic iron loading, splenic iron sparing, and elevated serum transferrin saturations. Thus, the mutant mice seemed to provide a faithful model for the abnormalities in iron homeostasis observed in patients with loss of TFR2. Heterozygous mice did not differ in any measured parameter from wildtype mice. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>5 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 HEMOCHROMATOSIS, TYPE 3</strong>
|
|
</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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TFR2, TYR250TER
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<br />
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|
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SNP: rs80338880,
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|
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gnomAD: rs80338880,
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|
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ClinVar: RCV000005711
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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>In 2 families from Sicily who met diagnostic criteria for hemochromatosis (HFE3; 604250) but were not linked to the HFE locus (235200), one of which was consanguineous, Camaschella et al. (2000) identified a C-to-G transversion in exon 6 at position 750 of the TFR2 cDNA sequence, resulting in a tyrosine (TAC)-to-stop (TAG) substitution at residue 250 (Y250X). This substitution created a MaeI site. All affected members of the consanguineous family were homozygous for Y250X, whereas obligate carriers were heterozygous. One patient in the nonconsanguineous family was homozygous for this mutation. Camaschella et al. (2000) did not find the Y250X mutation in 100 normal chromosomes or in 12 hemochromatosis patients who did not have mutations in HFE. </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 HEMOCHROMATOSIS, 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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TFR2, 1-BP INS, 84C
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<br />
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SNP: rs80338877,
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gnomAD: rs80338877,
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ClinVar: RCV000005712, RCV001381389
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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>In all affected members of a large inbred family in Campania in southern Italy segregating hemochromatosis (HFE3; 604250), Roetto et al. (2001) found a 1-bp insertion of a cytosine residue in homozygous state in exon 2 in a polyC tract (84-88 insC). The mutation resulted in a frameshift followed by a premature stop codon, a glu60-to-ter (E60X) substitution. Because of consanguinity, a pseudodominant pedigree pattern was observed in an affected father and his 3 affected children in one branch of the family. Heterozygosity was not associated with iron overload, even in individuals also heterozygous for H63D (613609.0002) at the HFE locus or for the beta-thalassemia trait. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0003 HEMOCHROMATOSIS, 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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TFR2, MET172LYS
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<br />
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SNP: rs80338879,
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gnomAD: rs80338879,
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ClinVar: RCV000005713
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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>In a family in which the proband had severe hemochromatosis (HFE3; 604250), Roetto et al. (2001) found homozygosity for a T-to-A transversion (515T-A) in exon 4 of TFR2 cDNA, resulting in a met172-to-lys (M172K) substitution of the protein. The proband had cirrhosis, hypogonadism, and cardiac disease. He had inherited beta-thalassemia in heterozygous state from his mother. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0004 HEMOCHROMATOSIS, TYPE 1, MODIFIER OF</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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TFR2, ARG455GLN
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<br />
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SNP: rs41303501,
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gnomAD: rs41303501,
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ClinVar: RCV000005714, RCV000020537, RCV000168108, RCV001081144, RCV003914812
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</span>
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<span class="mim-text-font">
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<p>Hofmann et al. (2002) studied 2 brothers who were homozygous for the common hemochromatosis-causing mutation of the HFE gene, cys282 to tyr (613609.0001). Direct nucleotide sequencing found a G-to-A transversion at nucleotide 1391, resulting in an arg455-to-gln (R455Q) amino acid change in the TFR2 gene. The R455Q mutation was present in only 1 of the brothers homozygous for C282Y; that brother had evidence of liver fibrosis, whereas the other brother did not. </p>
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<h4>
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<span class="mim-font">
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<strong>.0005 HEMOCHROMATOSIS, TYPE 3</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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TFR2, GLN690PRO
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<br />
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SNP: rs80338889,
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gnomAD: rs80338889,
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ClinVar: RCV000005715
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</span>
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<p>In a Portuguese man with severe hemochromatosis (HFE3; 604250) and in 2 family members, Mattman et al. (2002) found a gln690-to-pro (Q690P) mutation in the TFR2 gene. The patient presented at 29 years of age with fatigue, hypogonadotropic hypogonadism, hyperpigmentation, mild elevation of liver transaminases, and idiopathic thrombocytopenic purpura. He had markedly elevated serum iron indices and had had more than 12 g of iron removed via phlebotomy in the previous 4 years. Additional hematologic abnormalities included mild normocytic anemia and lymphopenia. He was heterozygous for the H63D mutation in the HFE gene (613609.0002). Mattman et al. (2002) stated that this patient was the only one of 89 non-C282Y hereditary chromatosis patients of predominately mixed European descent in whom mutation of the TFR2 gene had been found. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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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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<ol>
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<li>
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<p class="mim-text-font">
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Camaschella, C., Roetto, A., Cali, A., De Gobbi, M., Garozzo, G., Carella, M., Majorano, N., Totaro, A., Gasparini, P.
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<strong>The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22.</strong>
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Nature Genet. 25: 14-15, 2000.
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[PubMed: 10802645]
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[Full Text: https://doi.org/10.1038/75534]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Feder, J. N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D. A., Basava, A., Dormishian, F., Domingo, R., Jr., Ellis, M. C., Fullan, A., Hinton, L. M., Jones, N. L., and 21 others.
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<strong>A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.</strong>
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Nature Genet. 13: 399-408, 1996.
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[PubMed: 8696333]
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[Full Text: https://doi.org/10.1038/ng0896-399]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Fleming, R. E., Ahmann, J. R., Migas, M. C., Waheed, A., Koeffler, H. P., Kawabata, H., Britton, R. S., Bacon, B. R., Sly, W. S.
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<strong>Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis.</strong>
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Proc. Nat. Acad. Sci. 99: 10653-10658, 2002.
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[PubMed: 12134060]
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[Full Text: https://doi.org/10.1073/pnas.162360699]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Fleming, R. E., Migas, M. C., Holden, C. C., Waheed, A., Britton, R. S., Tomatsu, S., Bacon, B. R., Sly, W. S.
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<strong>Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis.</strong>
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Proc. Nat. Acad. Sci. 97: 2214-2219, 2000.
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[PubMed: 10681454]
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[Full Text: https://doi.org/10.1073/pnas.040548097]
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<li>
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<p class="mim-text-font">
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Hofmann, W.-K., Tong, X.-J., Ajioka, R. S., Kushner, J. P., Koeffler, H. P.
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<strong>Mutation analysis of transferrin-receptor 2 in patients with atypical hemochromatosis. (Letter)</strong>
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Blood 100: 1099-1100, 2002.
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[PubMed: 12150153]
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[Full Text: https://doi.org/10.1182/blood-2002-04-1077]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kawabata, H., Yang, R., Hirama, T., Vuong, P. T., Kawano, S., Gombart, A. F., Koeffler, H. P.
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<strong>Molecular cloning of transferrin receptor 2: a new member of the transferrin receptor-like family.</strong>
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J. Biol. Chem. 274: 20826-20832, 1999.
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[PubMed: 10409623]
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[Full Text: https://doi.org/10.1074/jbc.274.30.20826]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Mattman, A., Huntsman, D., Lockitch, G., Langlois, S., Buskard, N., Ralston, D., Butterfield, Y., Rodrigues, P., Jones, S., Porto, G., Marra, M., De Sousa, M., Vatcher, G.
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<strong>Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation.</strong>
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Blood 100: 1075-1077, 2002.
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[PubMed: 12130528]
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[Full Text: https://doi.org/10.1182/blood-2002-01-0133]
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</p>
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<li>
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<p class="mim-text-font">
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Roetto, A., Totaro, A., Piperno, A., Piga, A., Longo, F., Garozzo, G., Cali, A., De Gobbi, M., Gasparini, P., Camaschella, C.
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<strong>New mutations inactivating transferrin receptor 2 in hemochromatosis type 3.</strong>
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Blood 97: 2555-2560, 2001.
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[PubMed: 11313241]
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[Full Text: https://doi.org/10.1182/blood.v97.9.2555]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Wallace, D. F., Subramaniam, V. N.
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<strong>The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data.</strong>
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Genet. Med. 18: 618-626, 2016.
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[PubMed: 26633544]
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[Full Text: https://doi.org/10.1038/gim.2015.140]
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</p>
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</ol>
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<div>
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<br />
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Contributors:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 10/23/2018<br>Victor A. McKusick - updated : 3/6/2003<br>Victor A. McKusick - updated : 3/4/2003<br>Victor A. McKusick - updated : 9/27/2002<br>Victor A. McKusick - updated : 7/17/2001<br>Ada Hamosh - updated : 4/27/2000<br>Wilson H. Y. Lo - updated : 4/4/2000
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<span class="mim-text-font">
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Victor A. McKusick : 3/23/2000
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carol : 10/24/2018<br>alopez : 10/23/2018<br>alopez : 03/01/2018<br>carol : 10/21/2010<br>carol : 3/17/2006<br>terry : 9/8/2003<br>cwells : 3/6/2003<br>terry : 3/4/2003<br>cwells : 10/1/2002<br>carol : 9/27/2002<br>mcapotos : 8/7/2001<br>mcapotos : 7/26/2001<br>terry : 7/17/2001<br>alopez : 7/9/2001<br>carol : 7/6/2000<br>alopez : 4/28/2000<br>terry : 4/27/2000<br>carol : 4/6/2000<br>carol : 4/4/2000<br>mgross : 3/24/2000<br>mgross : 3/23/2000
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