3986 lines
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- *606464 - HEPCIDIN ANTIMICROBIAL PEPTIDE; HAMP
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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">*606464</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="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<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 role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/606464">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 role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<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=ENSG00000105697;t=ENST00000222304" 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=57817" 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=606464" 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 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=ENSG00000105697;t=ENST00000222304" 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_021175" 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_021175" 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=606464" 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=05925&isoform_id=05925_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/HAMP" 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/10241698,10720397,10863766,10863973,13182733,18088845,37182460,47522368,94717645,209407795,209407797,209407799,209407801,209407803,209407805,209407807,209407809,209407811,209407813,209407815,209407817,209407819,209407821,209407823,209407825,209407827,209407829,209407831,209407833,209407835,209407837,209407839,209407841,209407843,209407845,209407847,209407849,209407851,209407853,209407855,209407857,209407859,209407861,1243976861,1489342108,2230813986,2230813988,2230813990,2230813992,2230813994,2230813996,2230813998,2230814000,2245366740,2245366743,2245366746,2245366749,2245366752,2245366755,2245366758" 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/P81172" 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=57817" 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=ENSG00000105697;t=ENST00000222304" 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=HAMP" 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=HAMP" 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+57817" 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/HAMP" 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:57817" 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/57817" 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=chr19&hgg_gene=ENST00000222304.5&hgg_start=35282528&hgg_end=35285143&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://medlineplus.gov/genetics/gene/hamp" 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=606464[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=606464[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/ENSG00000105697" 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=HAMP" 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=HAMP" 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=HAMP" 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=HAMP&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/PA29182" 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:15598" 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/search?q=MGI:1933533 MGI:2153530" 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/HAMP#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/batch/summary?idType=MGI&ids=MGI:1933533 MGI:2153530" 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/57817/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=57817" 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-050726-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="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:57817" 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=HAMP&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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</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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606464
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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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HEPCIDIN ANTIMICROBIAL PEPTIDE; HAMP
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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LIVER-EXPRESSED ANTIMICROBIAL PEPTIDE; LEAP1<br />
|
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HEPCIDIN; HEPC
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=HAMP" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HAMP</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/19/576?start=-3&limit=10&highlight=576">19q13.12</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:35282528-35285143&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'})">19:35,282,528-35,285,143</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
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<div>
|
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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/19/576?start=-3&limit=10&highlight=576">
|
|
19q13.12
|
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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 2B
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/613313"> 613313 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<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">
|
|
<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/606464" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/606464" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</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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|
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<span class="mim-font">
|
|
<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.">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</span>
|
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</h4>
|
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
|
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</h4>
|
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</div>
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<p>The HAMP gene encodes hepcidin, an antimicrobial peptide and key iron regulatory hormone. Hepcidin is mainly produced by the liver during conditions of high iron, infection, or inflammation. Hepcidin controls plasma iron levels by binding to the iron exporter ferroportin (SLC40A1; <a href="/entry/604653">604653</a>) and inducing its degradation. By decreasing plasma iron levels, hepcidin provides an iron-restricted internal environment inhospitable to microbes, thereby contributing to innate immunity (summary by <a href="#10" class="mim-tip-reference" title="Malerba, M., Louis, S., Cuvellier, S., Shambat, S. M., Hua, C., Gomart, C., Fouet, A., Ortonne, N., Decousser, J.-W., Zinkernagel, A. S., Mathieu, J. R. R., Peyssonnaux, C. <strong>Epidermal hepcidin is required for neutrophil response to bacterial infection.</strong> J. Clin. Invest. 130: 329-334, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31600168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31600168</a>] [<a href="https://doi.org/10.1172/JCI126645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31600168">Malerba et al., 2020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31600168" 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>Antimicrobial peptides, which disrupt the cell membranes of cellular pathogens, are an important and conserved component of innate immunity in many species. By biochemical purification of blood ultrafiltrate using a cysteine alkylation assay and mass spectrometry, followed by micropeptide sequence and RT-PCR analysis as well as 5-prime and 3-prime RACE, <a href="#7" class="mim-tip-reference" title="Krause, A., Neitz, S., Magert, H.-J., Schulz, A., Forssmann, W.-G., Schulz-Knappe, P., Adermann, K. <strong>LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity.</strong> FEBS Lett. 480: 147-150, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11034317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11034317</a>] [<a href="https://doi.org/10.1016/s0014-5793(00)01920-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11034317">Krause et al. (2000)</a> isolated a cDNA encoding hepcidin antimicrobial peptide (HAMP), which the authors called LEAP1. The 84-amino acid protein contains a 24-residue N-terminal signal sequence and a pentaarginyl proteolysis site followed by the active C-terminal 25-amino acid peptide. The active peptide contains a unique 17-residue stretch with 8 cysteines forming 4 disulfide bridges. RT-PCR analysis detected broad expression of HAMP with very high levels in liver, moderate amounts in heart and brain, and lower amounts in lung and other tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11034317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By biochemical purification and amino acid sequence analysis of hepcidin peaks in urine, followed by EST database searching and 5-prime RACE, <a href="#19" class="mim-tip-reference" title="Park, C. H., Valore, E. V., Waring, A. J., Ganz, T. <strong>Hepcidin, a urinary antimicrobial peptide synthesized in the liver.</strong> J. Biol. Chem. 276: 7806-7810, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11113131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11113131</a>] [<a href="https://doi.org/10.1074/jbc.M008922200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11113131">Park et al. (2001)</a> also cloned HAMP, which they termed HEPC for its liver origin and antimicrobial properties. Northern blot analysis revealed expression of an intense 0.4-kb, as well as a weak 2.4-kb, transcript in adult and fetal liver. Weaker expression was detected in spinal cord and heart but not in other tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11113131" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The HAMP gene encodes a propeptide of 84 amino acids that undergoes enzymatic cleavage into mature peptides of 20, 22, and 25 amino acids (<a href="#19" class="mim-tip-reference" title="Park, C. H., Valore, E. V., Waring, A. J., Ganz, T. <strong>Hepcidin, a urinary antimicrobial peptide synthesized in the liver.</strong> J. Biol. Chem. 276: 7806-7810, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11113131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11113131</a>] [<a href="https://doi.org/10.1074/jbc.M008922200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11113131">Park et al., 2001</a>). Active peptides are rich in cysteines that form intramolecular bonds and stabilize the beta-sheet structure (<a href="#21" class="mim-tip-reference" title="Pigeon, C., Ilyin, G., Courselaud, B., Leroyer, P., Turlin, B., Brissot, P., Loreal, O. <strong>A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload.</strong> J. Biol. Chem. 276: 7811-7819, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11113132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11113132</a>] [<a href="https://doi.org/10.1074/jbc.M008923200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11113132">Pigeon et al., 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11113132+11113131" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By suppressive subtractive hybridization of iron-overloaded and control mouse livers, <a href="#21" class="mim-tip-reference" title="Pigeon, C., Ilyin, G., Courselaud, B., Leroyer, P., Turlin, B., Brissot, P., Loreal, O. <strong>A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload.</strong> J. Biol. Chem. 276: 7811-7819, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11113132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11113132</a>] [<a href="https://doi.org/10.1074/jbc.M008923200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11113132">Pigeon et al. (2001)</a> isolated a cDNA encoding mouse Hamp, which they designated Hepc. The deduced protein is 54% and 77% identical to the human and rat sequences, respectively, with complete conservation of the location of the cysteine residues. Northern blot analysis showed that dietary iron levels correlated with Hamp expression in the liver. Expression of mRNA also increased in liver and in cultured hepatocytes in response to stimulation with lipopolysaccharide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11113132" 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="#7" class="mim-tip-reference" title="Krause, A., Neitz, S., Magert, H.-J., Schulz, A., Forssmann, W.-G., Schulz-Knappe, P., Adermann, K. <strong>LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity.</strong> FEBS Lett. 480: 147-150, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11034317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11034317</a>] [<a href="https://doi.org/10.1016/s0014-5793(00)01920-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11034317">Krause et al. (2000)</a>, <a href="#19" class="mim-tip-reference" title="Park, C. H., Valore, E. V., Waring, A. J., Ganz, T. <strong>Hepcidin, a urinary antimicrobial peptide synthesized in the liver.</strong> J. Biol. Chem. 276: 7806-7810, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11113131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11113131</a>] [<a href="https://doi.org/10.1074/jbc.M008922200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11113131">Park et al. (2001)</a>, and <a href="#21" class="mim-tip-reference" title="Pigeon, C., Ilyin, G., Courselaud, B., Leroyer, P., Turlin, B., Brissot, P., Loreal, O. <strong>A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload.</strong> J. Biol. Chem. 276: 7811-7819, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11113132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11113132</a>] [<a href="https://doi.org/10.1074/jbc.M008923200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11113132">Pigeon et al. (2001)</a> determined that the HAMP gene contains 3 exons, with the final exon encoding the active peptide. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11034317+11113132+11113131" 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 genomic sequence analysis, <a href="#7" class="mim-tip-reference" title="Krause, A., Neitz, S., Magert, H.-J., Schulz, A., Forssmann, W.-G., Schulz-Knappe, P., Adermann, K. <strong>LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity.</strong> FEBS Lett. 480: 147-150, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11034317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11034317</a>] [<a href="https://doi.org/10.1016/s0014-5793(00)01920-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11034317">Krause et al. (2000)</a>, <a href="#19" class="mim-tip-reference" title="Park, C. H., Valore, E. V., Waring, A. J., Ganz, T. <strong>Hepcidin, a urinary antimicrobial peptide synthesized in the liver.</strong> J. Biol. Chem. 276: 7806-7810, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11113131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11113131</a>] [<a href="https://doi.org/10.1074/jbc.M008922200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11113131">Park et al. (2001)</a>, and <a href="#21" class="mim-tip-reference" title="Pigeon, C., Ilyin, G., Courselaud, B., Leroyer, P., Turlin, B., Brissot, P., Loreal, O. <strong>A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload.</strong> J. Biol. Chem. 276: 7811-7819, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11113132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11113132</a>] [<a href="https://doi.org/10.1074/jbc.M008923200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11113132">Pigeon et al. (2001)</a> mapped the HAMP gene to chromosome 19, in close proximity to USF2 (<a href="/entry/600390">600390</a>). <a href="#21" class="mim-tip-reference" title="Pigeon, C., Ilyin, G., Courselaud, B., Leroyer, P., Turlin, B., Brissot, P., Loreal, O. <strong>A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload.</strong> J. Biol. Chem. 276: 7811-7819, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11113132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11113132</a>] [<a href="https://doi.org/10.1074/jbc.M008923200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11113132">Pigeon et al. (2001)</a> also mapped the mouse gene to chromosome 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11034317+11113132+11113131" 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 functional analysis, <a href="#7" class="mim-tip-reference" title="Krause, A., Neitz, S., Magert, H.-J., Schulz, A., Forssmann, W.-G., Schulz-Knappe, P., Adermann, K. <strong>LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity.</strong> FEBS Lett. 480: 147-150, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11034317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11034317</a>] [<a href="https://doi.org/10.1016/s0014-5793(00)01920-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11034317">Krause et al. (2000)</a> determined that HAMP is most active against gram-positive bacteria, but also inhibits growth of certain yeast and gram-negative species with a spectrum resembling that of beta-defensin (DEFB1; <a href="/entry/602056">602056</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11034317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Park, C. H., Valore, E. V., Waring, A. J., Ganz, T. <strong>Hepcidin, a urinary antimicrobial peptide synthesized in the liver.</strong> J. Biol. Chem. 276: 7806-7810, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11113131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11113131</a>] [<a href="https://doi.org/10.1074/jbc.M008922200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11113131">Park et al. (2001)</a> detected antibacterial and antifungal activity by HAMP, but in contrast to alpha-defensin (DEFA1; <a href="/entry/125220">125220</a>), almost no toxicity against an erythroleukemia cell line. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11113131" 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>Animal models (see later) indicate that the antimicrobial peptide hepcidin is probably a key regulator of iron absorption in mammals. The regulation of intestinal iron absorption is crucial to avoid toxicity. Disruption of this regulation in hereditary hemochromatosis (<a href="/entry/235200">235200</a>) leads to iron overload, cirrhosis, cardiomyopathy, arthritis, and endocrine failure (<a href="#25" class="mim-tip-reference" title="Roetto, A., Papanikolaou, G., Politou, M., Alberti, F., Girelli, D., Christakis, J., Loukopoulos, D., Camaschella, C. <strong>Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis.</strong> Nature Genet. 33: 21-22, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12469120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12469120</a>] [<a href="https://doi.org/10.1038/ng1053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12469120">Roetto et al., 2003</a>). The apparent lack of susceptibility to infections in individuals with inactivated HAMP genes suggests that the antimicrobial role of HAMP is not critical for staving off infection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12469120" 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>Most individuals with hereditary hemochromatosis (<a href="/entry/235200">235200</a>) are homozygous with respect to a missense mutation that disrupts the conformation of HFE (<a href="/entry/613609">613609</a>), an atypical HLA class I molecule. Mice lacking Hfe or producing an Hfe protein carrying the common C282Y mutation (<a href="/entry/613609#0001">613609.0001</a>) develop hyperferremia and show high hepatic iron levels. In both humans and mice, hereditary hemochromatosis is associated with a paucity of iron in reticuloendothelial cells. <a href="#18" class="mim-tip-reference" title="Nicolas, G., Viatte, L., Lou, D.-Q., Bennoun, M., Beaumont, C., Kahn, A., Andrews, N. C., Vaulont, S. <strong>Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis.</strong> Nature Genet. 34: 97-101, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12704388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12704388</a>] [<a href="https://doi.org/10.1038/ng1150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12704388">Nicolas et al. (2003)</a> crossed Hfe -/- mice with transgenic mice overexpressing Hamp and found that Hamp inhibited the iron accumulation normally observed in the Hfe -/- mice. It had been suggested that Hfe modulates uptake of transferrin-bound iron by undifferentiated intestinal crypt cells, thereby programming the absorptive capacity of enterocytes derived from these cells. <a href="#18" class="mim-tip-reference" title="Nicolas, G., Viatte, L., Lou, D.-Q., Bennoun, M., Beaumont, C., Kahn, A., Andrews, N. C., Vaulont, S. <strong>Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis.</strong> Nature Genet. 34: 97-101, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12704388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12704388</a>] [<a href="https://doi.org/10.1038/ng1150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12704388">Nicolas et al. (2003)</a> proposed that their findings argued against the crypt programming model and suggested that failure of Hamp induction contributes to the pathogenesis of hemochromatosis, providing a rationale for the use of HAMP in the treatment of this disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12704388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Muckenthaler, M., Roy, C. N., Custodio, A. O., Minana, B., deGraaf, J., Montross, L. K., Andrews, N. C., Hentze, M. W. <strong>Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis.</strong> Nature Genet. 34: 102-107, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12704390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12704390</a>] [<a href="https://doi.org/10.1038/ng1152" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12704390">Muckenthaler et al. (2003)</a> likewise focused attention away from an exclusive role for the intestine in hereditary hemochromatosis. HFE deficiency in intestinal crypt cells had been thought to cause intestinal iron deficiency and greater expression of iron transporters such as SLC11A2 (<a href="/entry/600523">600523</a>) and SLC40A1 (<a href="/entry/604653">604653</a>). <a href="#13" class="mim-tip-reference" title="Muckenthaler, M., Roy, C. N., Custodio, A. O., Minana, B., deGraaf, J., Montross, L. K., Andrews, N. C., Hentze, M. W. <strong>Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis.</strong> Nature Genet. 34: 102-107, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12704390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12704390</a>] [<a href="https://doi.org/10.1038/ng1152" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12704390">Muckenthaler et al. (2003)</a> performed microarray assays to study changes in duodenal and hepatic gene expression in Hfe-deficient mice. They found unexpected alterations in the expression of Slc39a1 (the mouse ortholog of SLC40A1) and duodenal cytochrome b (CYBRD1; <a href="/entry/605745">605745</a>), which encode key iron transport proteins, and Hamp. They proposed that inappropriate regulatory cues from the liver underlie greater duodenal iron absorption, possibly involving the ferric reductase Cybrd1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12704390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In studies using cultured hepatocytes and mice, <a href="#14" class="mim-tip-reference" title="Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B. K., Ganz, T. <strong>IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin.</strong> J. Clin. Invest. 113: 1271-1276, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15124018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15124018</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15124018[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI20945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15124018">Nemeth et al. (2004)</a> demonstrated that interleukin-6 (IL6; <a href="/entry/147620">147620</a>) is the main mediator of hepcidin increase in inflammation, but is not required in the regulation of hepcidin by iron. In humans, infusion of IL6 rapidly increased hepcidin excretion with a concomitant decrease in serum iron and transferrin saturation. <a href="#14" class="mim-tip-reference" title="Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B. K., Ganz, T. <strong>IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin.</strong> J. Clin. Invest. 113: 1271-1276, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15124018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15124018</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15124018[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI20945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15124018">Nemeth et al. (2004)</a> concluded that IL6 is the necessary and sufficient cytokine for the induction of hepcidin during inflammation and that the IL6-hepcidin axis is responsible for the hypoferremia of inflammation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15124018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Nemeth, E., Tuttle, M. S., Powelson, J., Vaughn, M. B., Donovan, A., Ward, D. M., Ganz, T., Kaplan, J. <strong>Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.</strong> Science 306: 2090-2093, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15514116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15514116</a>] [<a href="https://doi.org/10.1126/science.1104742" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15514116">Nemeth et al. (2004)</a> reported that hepcidin bound to ferroportin (<a href="/entry/604653">604653</a>) in tissue culture cells. After binding, ferroportin was internalized and degraded, leading to decreased export of cellular iron. <a href="#15" class="mim-tip-reference" title="Nemeth, E., Tuttle, M. S., Powelson, J., Vaughn, M. B., Donovan, A., Ward, D. M., Ganz, T., Kaplan, J. <strong>Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.</strong> Science 306: 2090-2093, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15514116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15514116</a>] [<a href="https://doi.org/10.1126/science.1104742" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15514116">Nemeth et al. (2004)</a> postulated that the posttranslational regulation of ferroportin by hepcidin may complete a homeostatic loop regulating iron plasma levels and the tissue distribution of iron. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15514116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Robson, K. J. H., Merryweather-Clarke, A. T., Cadet, E., Viprakasit, V., Zaahl, M. G., Pointon, J. J., Weatherall, D. J., Rochette, J. <strong>Recent advances in understanding haemochromatosis: a transition state.</strong> J. Med. Genet. 41: 721-730, 2004. Note: Erratum: J. Med. Genet. 41: 959 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466004</a>] [<a href="https://doi.org/10.1136/jmg.2004.020644" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15466004">Robson et al. (2004)</a> reviewed the relationship between hemochromatosis and iron homeostasis in general and in host defenses. They noted that hepcidin is an acute phase protein and HFE is a major histocompatibility complex (MHC) class I-like molecule, which suggests that other players in a novel pathway of iron metabolism may be involved in a host defense pathway that limits iron availability and restricts growth of invading pathogens. The authors reviewed the evidence that the regulation of iron homeostasis and the inflammatory and immune responses are linked in a highly complex interactive system, many facets of which must have come under intense evolutionary pressure and therefore may show broad homology over many species. They are likely to exhibit wide genetic heterogeneity paralleled by variability of response to infection among different ethnic groups. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15466004" 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="#8" class="mim-tip-reference" title="Lee, P., Peng, H., Gelbart, T., Wang, L., Beutler, E. <strong>Regulation of hepcidin transcription by interleukin-1 and interleukin-6.</strong> Proc. Nat. Acad. Sci. 102: 1906-1910, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15684062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15684062</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15684062[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.0409808102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15684062">Lee et al. (2005)</a> showed that primary mouse hepatocytes could be stimulated by the cytokines IL6 (<a href="/entry/147620">147620</a>), IL1A (<a href="/entry/147760">147760</a>), and IL1B (<a href="/entry/147720">147720</a>) to express hepcidin message. IL10 (<a href="/entry/124092">124092</a>) had little to no stimulatory effect, and IFNB (<a href="/entry/147640">147640</a>) inhibited hepcidin transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15684062" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Tanno, T., Bhanu, N. V., Oneal, P. A., Goh, S.-H., Staker, P., Lee, Y. T., Moroney, J. W., Reed, C. H., Luban, N. L. C., Wang, R.-H., Eling, T. E., Childs, R., Ganz, T., Leitman, S. F., Fucharoen, S., Miller, J. L. <strong>High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin.</strong> Nature Med. 13: 1096-1101, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17721544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17721544</a>] [<a href="https://doi.org/10.1038/nm1629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17721544">Tanno et al. (2007)</a> hypothesized that accumulation of iron in the absence of blood transfusions in thalassemia patients may result from inappropriate suppression of the iron-regulating peptide hepcidin by an erythropoietic mechanism. To test this hypothesis, <a href="#27" class="mim-tip-reference" title="Tanno, T., Bhanu, N. V., Oneal, P. A., Goh, S.-H., Staker, P., Lee, Y. T., Moroney, J. W., Reed, C. H., Luban, N. L. C., Wang, R.-H., Eling, T. E., Childs, R., Ganz, T., Leitman, S. F., Fucharoen, S., Miller, J. L. <strong>High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin.</strong> Nature Med. 13: 1096-1101, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17721544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17721544</a>] [<a href="https://doi.org/10.1038/nm1629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17721544">Tanno et al. (2007)</a> examined erythroblast transcriptome profiles from 15 healthy nonthalassemic donors. Growth differentiation factor-15 (GDF15; <a href="/entry/605312">605312</a>) showed increased expression and secretion during erythroblast maturation. Healthy volunteers had mean GDF15 serum concentrations of 450 +/- 50 pg/ml. In comparison, individuals with beta-thalassemia syndromes had elevated GDF15 serum levels (mean 66,000 +/- 9,600 pg/ml; range 4,800-248,000 pg/ml; P less than 0.05) that were positively correlated with the levels of soluble transferrin receptor (<a href="/entry/190010">190010</a>), erythropoietin (<a href="/entry/133170">133170</a>), and ferritin (see <a href="/entry/134790">134790</a>). Serum from thalassemia patients suppressed hepcidin mRNA expression in primary human hepatocytes, and depletion of GDF15 reversed hepcidin suppression. <a href="#27" class="mim-tip-reference" title="Tanno, T., Bhanu, N. V., Oneal, P. A., Goh, S.-H., Staker, P., Lee, Y. T., Moroney, J. W., Reed, C. H., Luban, N. L. C., Wang, R.-H., Eling, T. E., Childs, R., Ganz, T., Leitman, S. F., Fucharoen, S., Miller, J. L. <strong>High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin.</strong> Nature Med. 13: 1096-1101, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17721544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17721544</a>] [<a href="https://doi.org/10.1038/nm1629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17721544">Tanno et al. (2007)</a> concluded that GDF15 overexpression arising from an expanded erythroid compartment contributes to iron overload in thalassemia syndromes by inhibiting hepcidin expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17721544" 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="Du, X., She, E., Gelbart, T., Truksa, J., Lee, P., Xia, Y., Khovananth, K., Mudd, S., Mann, N., Moresco, E. M. Y., Beutler, E., Beutler, B. <strong>The serine protease TMPRSS6 is required to sense iron deficiency.</strong> Science 320: 1088-1092, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18451267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18451267</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18451267[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1157121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18451267">Du et al. (2008)</a> identified TMPRSS6 (<a href="/entry/609862">609862</a>) as an essential component of a pathway that detects iron deficiency and blocks HAMP transcription, permitting enhanced dietary iron absorption. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18451267" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Weizer-Stern, O., Adamsky, K., Margalit, O., Ashur-Fabian, O., Givol, D., Amariglio, N., Rechavi, G. <strong>Hepcidin, a key regulator of iron metabolism, is transcriptionally activated by p53.</strong> Brit. J. Haemat. 138: 253-262, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17593032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17593032</a>] [<a href="https://doi.org/10.1111/j.1365-2141.2007.06638.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17593032">Weizer-Stern et al. (2007)</a> identified a putative p53 (TP53; <a href="/entry/191170">191170</a>) response element in the HAMP promoter. Using chromatin immunoprecipitation, reporter assays, and a temperature-sensitive p53 cell line, they demonstrated that p53 bound and activated the HAMP promoter. Activation of p53 increased HAMP expression, while silencing p53 decreased HAMP expression in human hepatoma cells. <a href="#31" class="mim-tip-reference" title="Weizer-Stern, O., Adamsky, K., Margalit, O., Ashur-Fabian, O., Givol, D., Amariglio, N., Rechavi, G. <strong>Hepcidin, a key regulator of iron metabolism, is transcriptionally activated by p53.</strong> Brit. J. Haemat. 138: 253-262, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17593032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17593032</a>] [<a href="https://doi.org/10.1111/j.1365-2141.2007.06638.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17593032">Weizer-Stern et al. (2007)</a> concluded that HAMP is a p53 target gene and suggested that iron deprivation via HAMP upregulation may be part of the p53-dependent defense mechanism against cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17593032" 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>Hepcidin is a key regulator of intestinal iron absorption whose expression is controlled by the bone morphogenetic protein (BMP; see <a href="/entry/112264">112264</a>) and SMAD (see <a href="/entry/601595">601595</a>) signaling pathway. <a href="#6" class="mim-tip-reference" title="Kautz, L., Meynard, D., Monnier, A., Darnaud, V., Bouvet, R., Wang, R. H., Deng, C., Vaulont, S., Mosser, J., Coppin, H., Roth, M. P. <strong>Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver.</strong> Blood 112: 1503-1509, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18539898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18539898</a>] [<a href="https://doi.org/10.1182/blood-2008-03-143354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18539898">Kautz et al. (2008)</a> performed a genomic screen in mice fed either an iron-enriched or iron-deficient diet, which demonstrated that in contrast to other BMP genes, Bmp6 mRNA expression was regulated by iron similar to Hamp mRNA expression, and suggested that BMP6 has a preponderant role in the activation of the SMAD signaling pathway leading to hepcidin synthesis in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18539898" 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>Hemojuvelin (HJV; <a href="/entry/608374">608374</a>) is a coreceptor for BMPs, and inhibition of endogenous BMP signaling reduces hepcidin expression and increases serum iron in mice (Babitt et al. (<a href="#2" class="mim-tip-reference" title="Babitt, J. L., Huang, F. W., Wrighting, D. M., Xia, Y., Sidis, Y., Samad, T. A., Campagna, J. A., Chung, R. T., Schneyer, A. L., Woolf, C. J., Andrews, N. C., Lin, H. Y. <strong>Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression.</strong> Nature Genet. 38: 531-539, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16604073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16604073</a>] [<a href="https://doi.org/10.1038/ng1777" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16604073">2006</a>, <a href="#3" class="mim-tip-reference" title="Babitt, J. L., Huang, F. W., Xia, Y., Sidis, Y., Andrews, N. C., Lin, H. Y. <strong>Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance.</strong> J. Clin. Invest. 117: 1933-1939, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17607365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17607365</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17607365[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI31342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17607365">2007</a>)). Using a protein pull-down assay, <a href="#1" class="mim-tip-reference" title="Andriopoulos, B., Jr., Corradini, E., Xia, Y., Faasse, S. A., Chen, S., Grgurevic, L., Knutson, M. D., Pietrangelo, A., Vukicevic, S., Lin, H. Y., Babitt, J. L. <strong>BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism.</strong> Nature Genet. 41: 482-487, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19252486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19252486</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19252486[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19252486">Andriopoulos et al. (2009)</a> demonstrated a direct physical interaction between recombinant soluble human HJV and BMP6. Intraperitoneal injection of BMP6 in mice caused increased hepatic hepcidin mRNA expression and reduced serum iron and transferrin (<a href="/entry/190000">190000</a>) saturation in a dose-dependent manner. Conversely, inhibition of endogenous Bmp6 in mice reduced hepcidin expression and increased serum iron. <a href="#1" class="mim-tip-reference" title="Andriopoulos, B., Jr., Corradini, E., Xia, Y., Faasse, S. A., Chen, S., Grgurevic, L., Knutson, M. D., Pietrangelo, A., Vukicevic, S., Lin, H. Y., Babitt, J. L. <strong>BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism.</strong> Nature Genet. 41: 482-487, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19252486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19252486</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19252486[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19252486">Andriopoulos et al. (2009)</a> concluded that BMP6 is an HJV ligand and an endogenous regulator of hepcidin expression and iron metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16604073+17607365+19252486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Vecchi, C., Montosi, G., Zhang, K., Lamberti, I., Duncan, S. A., Kaufman, R. J., Pietrangelo, A. <strong>ER stress controls iron metabolism through induction of hepcidin.</strong> Science 325: 877-880, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19679815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19679815</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19679815[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1176639" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19679815">Vecchi et al. (2009)</a> found that hepatic hepcidin gene expression was induced by endoplasmic reticulum (ER) stress in tunicamycin-treated mice. Mice with ER stress developed hypoferremia and sequestration of iron in macrophages, most prominent in the spleen. In vitro cellular studies showed that the HAMP promoter was activated by CREBH (<a href="/entry/611998">611998</a>). Crebh-null mice did not demonstrate increased Hamp activity in response to ER stress. The findings linked the intracellular response involved in protein quality control to innate immunity and iron homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19679815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using mass spectrometry, <a href="#20" class="mim-tip-reference" title="Peslova, G., Petrak, J., Kuzelova, K., Hrdy, I., Halada, P., Kuchel, P. W., Soe-Lin, S., Ponka, P., Sutak, R., Becker, E., Huang, M. L.-H., Rahmanto, Y. S., Richardson, D. R., Vyoral, D. <strong>Hepcidin, the hormone of iron metabolism, is bound specifically to alpha-2-macroglobulin in blood.</strong> Blood 113: 6225-6236, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19380872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19380872</a>] [<a href="https://doi.org/10.1182/blood-2009-01-201590" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19380872">Peslova et al. (2009)</a> showed that hepcidin in human plasma or serum was bound by albumin (ALB; <a href="/entry/103600">103600</a>) and by alpha-2-macroglobulin (A2M; <a href="/entry/103950">103950</a>). Binding of hepcidin to albumin was nonspecific and displayed nonsaturable kinetics. However, binding of hepcidin to A2M was specific. Scatchard analysis estimated 2 hepcidin-binding sites per inactive A2M molecule. Proteolytic activation of A2M resulted in a sigmoidal binding curve, suggesting high-affinity cooperative allosteric binding of 4 hepcidin molecules per active A2M molecule. The hepcidin-A2M complex, but not the hepcidin-albumin complex, decreased ferroportin expression in J774 murine macrophages more effectively than hepcidin alone. <a href="#20" class="mim-tip-reference" title="Peslova, G., Petrak, J., Kuzelova, K., Hrdy, I., Halada, P., Kuchel, P. W., Soe-Lin, S., Ponka, P., Sutak, R., Becker, E., Huang, M. L.-H., Rahmanto, Y. S., Richardson, D. R., Vyoral, D. <strong>Hepcidin, the hormone of iron metabolism, is bound specifically to alpha-2-macroglobulin in blood.</strong> Blood 113: 6225-6236, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19380872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19380872</a>] [<a href="https://doi.org/10.1182/blood-2009-01-201590" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19380872">Peslova et al. (2009)</a> hypothesized that A2M has a role in regulating hepcidin action by sequestration and subsequent release. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19380872" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Smith, C. L., Arvedson, T. L., Cooke, K. S., Dickmann, L. J., Forte, C., Li, H., Merriam, K. L., Perry, V. K., Tran, L., Rottman, J. B., Maxwell, J. R. <strong>IL-22 regulates iron availability in vivo through the induction of hepcidin.</strong> J. Immun. 191: 1845-1855, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23836059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23836059</a>] [<a href="https://doi.org/10.4049/jimmunol.1202716" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23836059">Smith et al. (2013)</a> showed that Il22 (<a href="/entry/605330">605330</a>), independent of Il6, could induce hepcidin production in mice, with a subsequent decrease in circulating serum iron and hemoglobin levels and a concomitant increase in splenic iron accumulation. This response was attenuated in the presence of the Il22r (IL22RA1; <a href="/entry/605457">605457</a>)-associated signaling kinase, Tyk2 (<a href="/entry/176941">176941</a>). Antibody blockade of hepcidin partially reversed the effects on iron biology caused by Il22r stimulation. <a href="#26" class="mim-tip-reference" title="Smith, C. L., Arvedson, T. L., Cooke, K. S., Dickmann, L. J., Forte, C., Li, H., Merriam, K. L., Perry, V. K., Tran, L., Rottman, J. B., Maxwell, J. R. <strong>IL-22 regulates iron availability in vivo through the induction of hepcidin.</strong> J. Immun. 191: 1845-1855, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23836059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23836059</a>] [<a href="https://doi.org/10.4049/jimmunol.1202716" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23836059">Smith et al. (2013)</a> proposed that IL22 is involved in regulating hepcidin production and iron homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23836059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Bessman, N. J., Mathieu, J. R. R., Renassia, C., Zhou, L., Fung, T. C., Fernandez, K. C., Austin, C., Moeller, J. B., Zumerle, S., Louis, S., Vaulont, S., Ajami, N. J., and 9 others. <strong>Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing.</strong> Science 368: 186-189, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32273468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32273468</a>] [<a href="https://doi.org/10.1126/science.aau6481" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32273468">Bessman et al. (2020)</a> found that hepcidin is required for tissue repair in the mouse intestine after experimental damage. This effect was independent of hepatocyte-derived hepcidin or systemic iron levels. Rather, <a href="#4" class="mim-tip-reference" title="Bessman, N. J., Mathieu, J. R. R., Renassia, C., Zhou, L., Fung, T. C., Fernandez, K. C., Austin, C., Moeller, J. B., Zumerle, S., Louis, S., Vaulont, S., Ajami, N. J., and 9 others. <strong>Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing.</strong> Science 368: 186-189, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32273468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32273468</a>] [<a href="https://doi.org/10.1126/science.aau6481" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32273468">Bessman et al. (2020)</a> found that conventional dendritic cells (cDCs) were the source of hepcidin that is induced by microbial stimulation in mice and is also prominent in the inflamed intestine of humans, and essential for tissue repair. cDC-derived hepcidin acted on ferroportin (SLC40A1; <a href="/entry/604653">604653</a>)-expressing phagocytes to promote local iron sequestration, which regulated the microbiota and consequently facilitated intestinal repair. <a href="#4" class="mim-tip-reference" title="Bessman, N. J., Mathieu, J. R. R., Renassia, C., Zhou, L., Fung, T. C., Fernandez, K. C., Austin, C., Moeller, J. B., Zumerle, S., Louis, S., Vaulont, S., Ajami, N. J., and 9 others. <strong>Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing.</strong> Science 368: 186-189, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32273468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32273468</a>] [<a href="https://doi.org/10.1126/science.aau6481" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32273468">Bessman et al. (2020)</a> concluded that their results identified a pathway whereby cDC-derived hepcidin promotes mucosal healing in the intestine through means of nutritional immunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32273468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#25" class="mim-tip-reference" title="Roetto, A., Papanikolaou, G., Politou, M., Alberti, F., Girelli, D., Christakis, J., Loukopoulos, D., Camaschella, C. <strong>Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis.</strong> Nature Genet. 33: 21-22, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12469120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12469120</a>] [<a href="https://doi.org/10.1038/ng1053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12469120">Roetto et al. (2003)</a> focused on the HAMP gene as the possible site of the defect in a form of juvenile hereditary hemochromatosis that was not linked to 1q (HFE2B; <a href="/entry/613313">613313</a>). Using microsatellite markers encompassing a region of 2.7 cM on 19q13 in one family, they identified a region of homozygosity in both probands. They then sequenced the HAMP coding region, exon-intron boundaries, and 5- and 3-prime untranslated regions in this family and a second family and identified 2 mutations (<a href="#0001">606464.0001</a>, <a href="#0002">606464.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12469120" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Merryweather-Clarke, A. T., Cadet, E., Bomford, A., Capron, D., Viprakasi, V., Miller, A., McHugh, P. J. Chapman, R. W., Pointon, J. J., Wimhurst, V. L. C., Livesey, K. J., Tanphaichitr, V., Rochette, J., Robson, K. J. H. <strong>Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis.</strong> Hum. Molec. Genet. 12: 2241-2247, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915468</a>] [<a href="https://doi.org/10.1093/hmg/ddg225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915468">Merryweather-Clarke et al. (2003)</a> described 2 families who exhibited digenic inheritance of hemochromatosis. In family A, the proband had a juvenile hemochromatosis (<a href="/entry/613313">613313</a>) phenotype and was heterozygous for the C282Y mutation in the HFE gene (<a href="/entry/613609#0001">613609.0001</a>) as well as a HAMP frameshift mutation (<a href="#0003">606464.0003</a>). The proband's unaffected mother was also heterozygous for the HAMP frameshift mutation, but lacked the HFE C282Y mutation and was heterozygous for the HFE H63D mutation (<a href="/entry/613609#0002">613609.0002</a>). In family B, there was a correlation between severity of iron overload, heterozygosity for a HAMP G71D mutation (<a href="#0004">606464.0004</a>), and heterozygosity or homozygosity for the HFE C282Y mutation. The authors proposed that the phenotype of C282Y heterozygotes and homozygotes may be modified by heterozygosity for mutations which disrupt the function of hepcidin in iron homeostasis, with the severity of iron overload corresponding to the severity of the HAMP mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="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 (<a href="/entry/604720">604720</a>)-, HFE2 (<a href="/entry/608374">608374</a>)-, and HAMP-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><a href="#16" class="mim-tip-reference" title="Nicolas, G., Bennoun, M., Devaux, I., Beaumont, C., Grandchamp, B., Kahn, A., Vaulont, S. <strong>Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice.</strong> Proc. Nat. Acad. Sci. 98: 8780-8785, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11447267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11447267</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11447267[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.151179498" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11447267">Nicolas et al. (2001)</a> found that hepcidin gene expression was totally inhibited in mice exhibiting iron overload consequent to targeted disruption of the Usf2 gene. In these Usf2 knockout mice, the development of iron overload was strikingly similar to that observed in human hereditary hemochromatosis and in mice with knockout of the Hfe gene (<a href="/entry/613609">613609</a>), the mouse model of hemochromatosis; iron accumulated in parenchymal cells (in particular, liver and pancreas), whereas the reticuloendothelial system was spared from this iron loading. <a href="#16" class="mim-tip-reference" title="Nicolas, G., Bennoun, M., Devaux, I., Beaumont, C., Grandchamp, B., Kahn, A., Vaulont, S. <strong>Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice.</strong> Proc. Nat. Acad. Sci. 98: 8780-8785, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11447267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11447267</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11447267[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.151179498" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11447267">Nicolas et al. (2001)</a> suggested that this phenotypic trait could be attributed to the absence of hepcidin in the Usf2 knockout mice. They conjectured that the reverse situation, namely overexpression of hepcidin, might result in phenotypic traits of iron deficiency. <a href="#17" class="mim-tip-reference" title="Nicolas, G., Bennoun, M., Porteu, A., Mativet, S., Beaumont, C., Grandchamp, B., Sirito, M., Sawadogo, M., Kahn, A., Vaulont, S. <strong>Severe iron deficiency anemia in transgenic mice expressing liver hepcidin.</strong> Proc. Nat. Acad. Sci. 99: 4596-4601, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11930010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11930010</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11930010[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.072632499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11930010">Nicolas et al. (2002)</a> addressed this question by generating transgenic mice expressing hepcidin under the control of the liver-specific transthyretin (TTR; <a href="/entry/176300">176300</a>) promoter. They found that most of the transgenic mice were born with pale skin and died within a few hours after birth. The animals had decreased body iron levels and presented severe microcytic hypochromic anemia. Three mosaic transgenic animals that survived were unequivocally identified by physical features, including reduced body size, pallor, and hairless and crumpled skin. These pleiotropic effects were found to be associated with erythrocyte abnormalities, with marked anisocytosis, poikilocytosis, and hypochromia, which are features of iron-deficiency anemia. These results supported the proposed role of hepcidin as an iron-regulatory hormone. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11447267+11930010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In contrast to the human genome, which contains only 1 copy of the hepcidin gene, the mouse genome contains 2 highly similar hepcidin genes, Hepc1 and Hepc2, which are, however, considerably divergent at the level of the corresponding mature 25-amino acid peptide. <a href="#17" class="mim-tip-reference" title="Nicolas, G., Bennoun, M., Porteu, A., Mativet, S., Beaumont, C., Grandchamp, B., Sirito, M., Sawadogo, M., Kahn, A., Vaulont, S. <strong>Severe iron deficiency anemia in transgenic mice expressing liver hepcidin.</strong> Proc. Nat. Acad. Sci. 99: 4596-4601, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11930010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11930010</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11930010[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.072632499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11930010">Nicolas et al. (2002)</a> established the role of hepcidin in iron metabolism by generating transgenic mice overexpressing Hepc1 in the liver. A severe iron-deficient anemia phenotype resulted. <a href="#9" class="mim-tip-reference" title="Lou, D.-Q., Nicolas, G., Lesbordes, J.-C., Viatte, L., Grimber, G., Szajnert, M.-F., Kahn, A., Vaulont, S. <strong>Functional differences between hepcidin 1 and 2 in transgenic mice.</strong> Blood 103: 2816-2821, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14604961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14604961</a>] [<a href="https://doi.org/10.1182/blood-2003-07-2524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14604961">Lou et al. (2004)</a> reported that, in contrast to the Hepc1 transgenic mice, none of the Hepc2 transgenic animals suffered from anemia. They all developed normally with hematologic parameters similar to the nontransgenic littermates. Hepc2 transgenic mRNA levels were found to be very high for all lines, compared with the level of Hepc1 transgene mRNA necessary to produce severe anemia. These data provided evidence that Hepc2 does not act on iron metabolism like Hepc1 and gave clues for the identification of amino acids important for the iron-regulatory action of the mature 25-amino acid peptide. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11930010+14604961" 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="#23" class="mim-tip-reference" title="Rivera, S., Liu, L., Nemeth, E., Gabayan, V., Sorensen, O. E., Ganz, T. <strong>Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia.</strong> Blood 105: 1797-1802, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15479721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15479721</a>] [<a href="https://doi.org/10.1182/blood-2004-08-3375" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15479721">Rivera et al. (2005)</a> found that treatment with human hepcidin induced acute hypoferremia in mice, demonstrating the bioactivity of human hepcidin in mice. To investigate the chronic effects of hepcidin, the authors designed tumor xenografts expressing high levels of human hepcidin in mice. Mice with hepcidin-producing tumors developed anemia even when maintained on a high-iron diet. Furthermore, liver iron stores were significantly increased by hepcidin, and iron was present predominantly in hepatocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15479721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Ramey, G., Faye, A., Durel, B., Viollet, B., Vaulont, S. <strong>Iron overload in Hepc1-/- mice is not impairing glucose homeostasis.</strong> FEBS Lett. 581: 1053-1057, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17316628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17316628</a>] [<a href="https://doi.org/10.1016/j.febslet.2007.02.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17316628">Ramey et al. (2007)</a> found that Hepc1 -/- mice accumulated iron in exocrine pancreas. Iron overload in exocrine pancreas did not affect production and secretion of insulin. Furthermore, glucose homeostasis was not impaired, whole body insulin sensitivity was preserved, and Hepc1 -/- mice did not develop insulin resistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17316628" 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>Iron excess is regulated through a pathway involving hemojuvelin that stimulates expression of hepcidin, whereas iron attenuation is countered through a pathway involving TMPRSS6 that suppresses expression of hepcidin. <a href="#28" class="mim-tip-reference" title="Truksa, J., Gelbart, T., Peng, H., Beutler, E., Beutler, B., Lee, P. <strong>Suppression of the hepcidin-encoding gene Hamp permits iron overload in mice lacking both hemojuvelin and matriptase-2/TMPRSS6.</strong> Brit. J. Haemat. 147: 571-581, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19751239/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19751239</a>] [<a href="https://doi.org/10.1111/j.1365-2141.2009.07873.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19751239">Truksa et al. (2009)</a> found that double-knockout mice lacking both Tmprss6 and hemojuvelin exhibited low hepcidin expression and iron overload. However, double-knockout mice showed lower levels of iron in heart than hemojuvelin -/- mice, demonstrating a possible cardioprotective effect resulting from loss of Tmprss6. This phenotype supported a model in which hemojuvelin is a major substrate for Tmprss6 protease activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19751239" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Malerba, M., Louis, S., Cuvellier, S., Shambat, S. M., Hua, C., Gomart, C., Fouet, A., Ortonne, N., Decousser, J.-W., Zinkernagel, A. S., Mathieu, J. R. R., Peyssonnaux, C. <strong>Epidermal hepcidin is required for neutrophil response to bacterial infection.</strong> J. Clin. Invest. 130: 329-334, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31600168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31600168</a>] [<a href="https://doi.org/10.1172/JCI126645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31600168">Malerba et al. (2020)</a> found that hepcidin production was induced in skin of patients with group A Streptococcus (GAS) necrotizing fasciitis (NF), as well as in GAS-infected skin of mice, especially in keratinocytes. Keratinocyte-specific hepcidin deficiency failed to restrict systemic spread of GAS infection from an initial tissue focus into bloodstream and systemic organs of mice. However, hepcidin did not have a direct antimicrobial effect on bacteria, but instead promoted production of Cxcl1 (<a href="/entry/155730">155730</a>) in keratinocytes, resulting in neutrophil recruitment. Unlike Cxcl1, hepcidin was resistant to degradation by major GAS proteases, suggesting it could be used to promote production of Cxcl1 or maintain steady-state levels of Cxcl1 in infected tissue. Indeed, injection of hepcidin at the infection site limited or prevented systemic spread of GAS infection in mice, suggesting that hepcidin agonists may have a therapeutic role in NF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31600168" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<p>In a family with juvenile hereditary hemochromatosis (HFE2B; <a href="/entry/613313">613313</a>), <a href="#25" class="mim-tip-reference" title="Roetto, A., Papanikolaou, G., Politou, M., Alberti, F., Girelli, D., Christakis, J., Loukopoulos, D., Camaschella, C. <strong>Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis.</strong> Nature Genet. 33: 21-22, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12469120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12469120</a>] [<a href="https://doi.org/10.1038/ng1053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12469120">Roetto et al. (2003)</a> found a C-to-T transition at position 166 in exon 3 of HAMP cDNA (166C-T), which changed arginine at position 56 to a stop codon (R56X). The R56X amino acid change occurred in a pentaarginine (residues 55-59) basic domain, which is thought to be the recognition site for pro-hormone convertases, and produces a truncated prohepcidin lacking all mature peptide sequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12469120" 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">rs1422879641 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1422879641;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1422879641" 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=rs1422879641" 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=RCV000004506" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004506" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004506</a>
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<p><a href="#12" class="mim-tip-reference" title="Merryweather-Clarke, A. T., Cadet, E., Bomford, A., Capron, D., Viprakasi, V., Miller, A., McHugh, P. J. Chapman, R. W., Pointon, J. J., Wimhurst, V. L. C., Livesey, K. J., Tanphaichitr, V., Rochette, J., Robson, K. J. H. <strong>Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis.</strong> Hum. Molec. Genet. 12: 2241-2247, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915468</a>] [<a href="https://doi.org/10.1093/hmg/ddg225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915468">Merryweather-Clarke et al. (2003)</a> reported an individual with a juvenile hemochromatosis (<a href="/entry/613313">613313</a>) phenotype who was heterozygous for the C282Y mutation in the HFE gene (<a href="/entry/613609#0001">613609.0001</a>) as well as a 4-bp HAMP frameshift mutation. The mutation deleted the last codon of exon 2 (met50) as well as the first base of the splice donor site of intron 2 (IVS+1(-G)). The mutation was predicted to result in retention of the splice consensus site, but altered the reading frame, extending it beyond the end of the normal transcript. The proband's unaffected mother was also heterozygous for the HAMP frameshift mutation, but lacked the HFE C282Y mutation and was heterozygous for the HFE H63D mutation (<a href="/entry/613609#0002">613609.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915468" 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 2A, MODIFIER OF</strong>
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HAMP, GLY71ASP
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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> rs104894696 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894696;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/rs104894696?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=rs104894696" 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=rs104894696" 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=RCV000004507 OR RCV000599701 OR RCV000990194 OR RCV001086432 OR RCV001127434 OR RCV003974795" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004507, RCV000599701, RCV000990194, RCV001086432, RCV001127434, RCV003974795" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004507...</a>
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<p><a href="#12" class="mim-tip-reference" title="Merryweather-Clarke, A. T., Cadet, E., Bomford, A., Capron, D., Viprakasi, V., Miller, A., McHugh, P. J. Chapman, R. W., Pointon, J. J., Wimhurst, V. L. C., Livesey, K. J., Tanphaichitr, V., Rochette, J., Robson, K. J. H. <strong>Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis.</strong> Hum. Molec. Genet. 12: 2241-2247, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915468</a>] [<a href="https://doi.org/10.1093/hmg/ddg225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915468">Merryweather-Clarke et al. (2003)</a> reported a 2-generation family with juvenile hemochromatosis (<a href="/entry/602390">602390</a>) in which the proband and his sister were homozygous for a C282Y mutation in HFE (<a href="/entry/253200#0001">253200.0001</a>) and heterozygous for a gly71-to-asp (G71D) mutation in the HAMP gene. The father was heterozygous for both HFE C282Y and HAMP G71D. There was a correlation between severity of iron overload, heterozygosity for HAMP G71D, and heterozygosity or homozygosity for the HFE C282Y mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915468" 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 2B</strong>
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HAMP, +14G-A, 5-PRIME UTR
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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> rs944843686 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs944843686;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/rs944843686?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=rs944843686" 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=rs944843686" 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=RCV000004508 OR RCV003588556" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004508, RCV003588556" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004508...</a>
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<p>In a 29-year-old Portuguese man with juvenile hemochromatosis (<a href="/entry/602390">602390</a>), <a href="#11" class="mim-tip-reference" title="Matthes, T., Aguilar-Martinez, P., Pizzi-Bosman, L., Darbellay, R., Rubbia-Brandt, L., Giostra, E., Michel, M., Ganz, T., Beris, P. <strong>Severe hemochromatosis in a Portuguese family associated with a new mutation in the 5-prime-UTR of the HAMP gene.</strong> Blood 104: 2181-2183, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15198949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15198949</a>] [<a href="https://doi.org/10.1182/blood-2004-01-0332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15198949">Matthes et al. (2004)</a> identified a homozygous G-to-A transition at position +14 of the 5-prime UTR relative to the cap site of the mRNA for HAMP. The mutation created a new initiation codon at position +14 of the 5-prime UTR, which induced a shift of the reading frame and the generation of an abnormal protein. This protein was probably unstable or otherwise degraded, as it was not found on bidirectional protein gel electrophoresis. The patient was diagnosed with insulin-dependent diabetes mellitus and severe heart failure; he exhibited skin hyperpigmentation, hepatosplenomegaly, and hypogonadism. The patient's 24-year-old sister was homozygous for the same mutation, whereas both parents and a cousin were found to be heterozygous, with no signs of iron overload. The sister had no clinical findings, but laboratory tests showed increased transaminases and iron overload. Liver biopsy showed moderate, predominantly periportal, hepatocellular siderosis without cirrhosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15198949" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Andriopoulos2009" class="mim-anchor"></a>
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Andriopoulos, B., Jr., Corradini, E., Xia, Y., Faasse, S. A., Chen, S., Grgurevic, L., Knutson, M. D., Pietrangelo, A., Vukicevic, S., Lin, H. Y., Babitt, J. L.
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<strong>BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism.</strong>
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Nature Genet. 41: 482-487, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19252486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19252486</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19252486[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=19252486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.335" target="_blank">Full Text</a>]
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Babitt, J. L., Huang, F. W., Wrighting, D. M., Xia, Y., Sidis, Y., Samad, T. A., Campagna, J. A., Chung, R. T., Schneyer, A. L., Woolf, C. J., Andrews, N. C., Lin, H. Y.
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<strong>Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression.</strong>
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Nature Genet. 38: 531-539, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16604073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16604073</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16604073" 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/ng1777" target="_blank">Full Text</a>]
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<a id="Babitt2007" class="mim-anchor"></a>
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Babitt, J. L., Huang, F. W., Xia, Y., Sidis, Y., Andrews, N. C., Lin, H. Y.
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<strong>Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance.</strong>
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J. Clin. Invest. 117: 1933-1939, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17607365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17607365</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17607365[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=17607365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI31342" target="_blank">Full Text</a>]
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<a id="Bessman2020" class="mim-anchor"></a>
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Bessman, N. J., Mathieu, J. R. R., Renassia, C., Zhou, L., Fung, T. C., Fernandez, K. C., Austin, C., Moeller, J. B., Zumerle, S., Louis, S., Vaulont, S., Ajami, N. J., and 9 others.
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<strong>Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing.</strong>
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Science 368: 186-189, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32273468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32273468</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32273468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.aau6481" target="_blank">Full Text</a>]
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Du, X., She, E., Gelbart, T., Truksa, J., Lee, P., Xia, Y., Khovananth, K., Mudd, S., Mann, N., Moresco, E. M. Y., Beutler, E., Beutler, B.
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<strong>The serine protease TMPRSS6 is required to sense iron deficiency.</strong>
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Science 320: 1088-1092, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18451267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18451267</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18451267[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=18451267" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1157121" target="_blank">Full Text</a>]
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<a id="Kautz2008" class="mim-anchor"></a>
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Kautz, L., Meynard, D., Monnier, A., Darnaud, V., Bouvet, R., Wang, R. H., Deng, C., Vaulont, S., Mosser, J., Coppin, H., Roth, M. P.
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<strong>Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver.</strong>
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Blood 112: 1503-1509, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18539898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18539898</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18539898" 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-2003-07-2524" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI126645" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1182/blood-2004-01-0332" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg225" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1152" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI20945" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1104742" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.072632499" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1150" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M008922200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1182/blood-2009-01-201590" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.febslet.2007.02.002" target="_blank">Full Text</a>]
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<a id="23" class="mim-anchor"></a>
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<a id="Rivera2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rivera, S., Liu, L., Nemeth, E., Gabayan, V., Sorensen, O. E., Ganz, T.
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<strong>Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia.</strong>
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Blood 105: 1797-1802, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15479721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15479721</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15479721" 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-2004-08-3375" target="_blank">Full Text</a>]
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<a id="24" class="mim-anchor"></a>
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<a id="Robson2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Robson, K. J. H., Merryweather-Clarke, A. T., Cadet, E., Viprakasit, V., Zaahl, M. G., Pointon, J. J., Weatherall, D. J., Rochette, J.
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<strong>Recent advances in understanding haemochromatosis: a transition state.</strong>
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J. Med. Genet. 41: 721-730, 2004. Note: Erratum: J. Med. Genet. 41: 959 only, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466004</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15466004" 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/10.1136/jmg.2004.020644" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="Roetto2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Roetto, A., Papanikolaou, G., Politou, M., Alberti, F., Girelli, D., Christakis, J., Loukopoulos, D., Camaschella, C.
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<strong>Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis.</strong>
|
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Nature Genet. 33: 21-22, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12469120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12469120</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12469120" 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/ng1053" target="_blank">Full Text</a>]
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Smith2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Smith, C. L., Arvedson, T. L., Cooke, K. S., Dickmann, L. J., Forte, C., Li, H., Merriam, K. L., Perry, V. K., Tran, L., Rottman, J. B., Maxwell, J. R.
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<strong>IL-22 regulates iron availability in vivo through the induction of hepcidin.</strong>
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J. Immun. 191: 1845-1855, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23836059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23836059</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23836059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.4049/jimmunol.1202716" target="_blank">Full Text</a>]
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<a id="Tanno2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tanno, T., Bhanu, N. V., Oneal, P. A., Goh, S.-H., Staker, P., Lee, Y. T., Moroney, J. W., Reed, C. H., Luban, N. L. C., Wang, R.-H., Eling, T. E., Childs, R., Ganz, T., Leitman, S. F., Fucharoen, S., Miller, J. L.
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<strong>High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin.</strong>
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Nature Med. 13: 1096-1101, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17721544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17721544</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17721544" 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/nm1629" target="_blank">Full Text</a>]
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<a id="28" class="mim-anchor"></a>
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<a id="Truksa2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Truksa, J., Gelbart, T., Peng, H., Beutler, E., Beutler, B., Lee, P.
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<strong>Suppression of the hepcidin-encoding gene Hamp permits iron overload in mice lacking both hemojuvelin and matriptase-2/TMPRSS6.</strong>
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Brit. J. Haemat. 147: 571-581, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19751239/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19751239</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19751239" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1365-2141.2009.07873.x" target="_blank">Full Text</a>]
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<a id="29" class="mim-anchor"></a>
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<a id="Vecchi2009" class="mim-anchor"></a>
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Vecchi, C., Montosi, G., Zhang, K., Lamberti, I., Duncan, S. A., Kaufman, R. J., Pietrangelo, A.
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<strong>ER stress controls iron metabolism through induction of hepcidin.</strong>
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Science 325: 877-880, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19679815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19679815</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19679815[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=19679815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1176639" target="_blank">Full Text</a>]
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<a id="30" class="mim-anchor"></a>
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<a id="Wallace2016" class="mim-anchor"></a>
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<div class="">
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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: <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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<li>
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<a id="31" class="mim-anchor"></a>
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<a id="Weizer-Stern2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weizer-Stern, O., Adamsky, K., Margalit, O., Ashur-Fabian, O., Givol, D., Amariglio, N., Rechavi, G.
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<strong>Hepcidin, a key regulator of iron metabolism, is transcriptionally activated by p53.</strong>
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Brit. J. Haemat. 138: 253-262, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17593032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17593032</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17593032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1365-2141.2007.06638.x" target="_blank">Full Text</a>]
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</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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Matthew B. Gross - updated : 01/06/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 01/06/2021<br>Ada Hamosh - updated : 04/28/2020<br>Ada Hamosh - updated : 10/23/2018<br>Paul J. Converse - updated : 8/13/2014<br>Patricia A. Hartz - updated : 11/2/2010<br>Cassandra L. Kniffin - updated : 8/24/2009<br>Patricia A. Hartz - updated : 4/23/2009<br>Patricia A. Hartz - updated : 7/11/2008<br>Ada Hamosh - updated : 6/10/2008<br>Ada Hamosh - updated : 3/26/2008<br>Patricia A. Hartz - updated : 6/7/2005<br>Victor A. McKusick - updated : 2/17/2005<br>Ada Hamosh - updated : 1/27/2005<br>Victor A. McKusick - updated : 12/20/2004<br>Victor A. McKusick - updated : 8/23/2004<br>Marla J. F. O'Neill - updated : 7/1/2004<br>Victor A. McKusick - updated : 1/2/2004<br>George E. Tiller - updated : 11/13/2003<br>Victor A. McKusick - updated : 4/18/2003<br>Victor A. McKusick - updated : 12/10/2002<br>Victor A. McKusick - updated : 9/23/2002
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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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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Paul J. Converse : 11/16/2001
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<a id="editHistory" class="mim-anchor"></a>
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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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mgross : 01/06/2021
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</span>
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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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mgross : 01/06/2021<br>alopez : 04/28/2020<br>alopez : 10/23/2018<br>alopez : 09/07/2016<br>mgross : 08/18/2014<br>mcolton : 8/13/2014<br>terry : 11/28/2012<br>mgross : 11/5/2010<br>terry : 11/2/2010<br>carol : 10/21/2010<br>alopez : 3/23/2010<br>wwang : 8/25/2009<br>ckniffin : 8/24/2009<br>alopez : 4/23/2009<br>mgross : 7/11/2008<br>terry : 7/11/2008<br>terry : 6/10/2008<br>alopez : 3/27/2008<br>alopez : 3/27/2008<br>terry : 3/26/2008<br>mgross : 3/10/2008<br>wwang : 6/17/2005<br>wwang : 6/8/2005<br>terry : 6/7/2005<br>mgross : 4/20/2005<br>tkritzer : 2/23/2005<br>terry : 2/17/2005<br>wwang : 2/3/2005<br>terry : 1/27/2005<br>tkritzer : 1/10/2005<br>terry : 12/20/2004<br>tkritzer : 9/1/2004<br>terry : 8/23/2004<br>carol : 7/2/2004<br>terry : 7/1/2004<br>tkritzer : 1/8/2004<br>terry : 1/2/2004<br>cwells : 11/13/2003<br>alopez : 4/30/2003<br>alopez : 4/25/2003<br>alopez : 4/22/2003<br>terry : 4/18/2003<br>alopez : 1/2/2003<br>alopez : 12/10/2002<br>terry : 12/10/2002<br>tkritzer : 11/19/2002<br>cwells : 9/23/2002<br>carol : 11/16/2001
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</span>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 606464
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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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HEPCIDIN ANTIMICROBIAL PEPTIDE; HAMP
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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LIVER-EXPRESSED ANTIMICROBIAL PEPTIDE; LEAP1<br />
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HEPCIDIN; HEPC
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: HAMP</em></strong>
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</span>
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</p>
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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: 19q13.12
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:35,282,528-35,285,143 </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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19q13.12
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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 2B
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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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613313
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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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</table>
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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>Description</strong>
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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 HAMP gene encodes hepcidin, an antimicrobial peptide and key iron regulatory hormone. Hepcidin is mainly produced by the liver during conditions of high iron, infection, or inflammation. Hepcidin controls plasma iron levels by binding to the iron exporter ferroportin (SLC40A1; 604653) and inducing its degradation. By decreasing plasma iron levels, hepcidin provides an iron-restricted internal environment inhospitable to microbes, thereby contributing to innate immunity (summary by Malerba et al., 2020). </p>
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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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<span class="mim-text-font">
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<p>Antimicrobial peptides, which disrupt the cell membranes of cellular pathogens, are an important and conserved component of innate immunity in many species. By biochemical purification of blood ultrafiltrate using a cysteine alkylation assay and mass spectrometry, followed by micropeptide sequence and RT-PCR analysis as well as 5-prime and 3-prime RACE, Krause et al. (2000) isolated a cDNA encoding hepcidin antimicrobial peptide (HAMP), which the authors called LEAP1. The 84-amino acid protein contains a 24-residue N-terminal signal sequence and a pentaarginyl proteolysis site followed by the active C-terminal 25-amino acid peptide. The active peptide contains a unique 17-residue stretch with 8 cysteines forming 4 disulfide bridges. RT-PCR analysis detected broad expression of HAMP with very high levels in liver, moderate amounts in heart and brain, and lower amounts in lung and other tissues. </p><p>By biochemical purification and amino acid sequence analysis of hepcidin peaks in urine, followed by EST database searching and 5-prime RACE, Park et al. (2001) also cloned HAMP, which they termed HEPC for its liver origin and antimicrobial properties. Northern blot analysis revealed expression of an intense 0.4-kb, as well as a weak 2.4-kb, transcript in adult and fetal liver. Weaker expression was detected in spinal cord and heart but not in other tissues. </p><p>The HAMP gene encodes a propeptide of 84 amino acids that undergoes enzymatic cleavage into mature peptides of 20, 22, and 25 amino acids (Park et al., 2001). Active peptides are rich in cysteines that form intramolecular bonds and stabilize the beta-sheet structure (Pigeon et al., 2001). </p><p>By suppressive subtractive hybridization of iron-overloaded and control mouse livers, Pigeon et al. (2001) isolated a cDNA encoding mouse Hamp, which they designated Hepc. The deduced protein is 54% and 77% identical to the human and rat sequences, respectively, with complete conservation of the location of the cysteine residues. Northern blot analysis showed that dietary iron levels correlated with Hamp expression in the liver. Expression of mRNA also increased in liver and in cultured hepatocytes in response to stimulation with lipopolysaccharide. </p>
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</span>
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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>Krause et al. (2000), Park et al. (2001), and Pigeon et al. (2001) determined that the HAMP gene contains 3 exons, with the final exon encoding the active peptide. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By genomic sequence analysis, Krause et al. (2000), Park et al. (2001), and Pigeon et al. (2001) mapped the HAMP gene to chromosome 19, in close proximity to USF2 (600390). Pigeon et al. (2001) also mapped the mouse gene to chromosome 7. </p>
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</span>
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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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</h4>
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<span class="mim-text-font">
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<p>By functional analysis, Krause et al. (2000) determined that HAMP is most active against gram-positive bacteria, but also inhibits growth of certain yeast and gram-negative species with a spectrum resembling that of beta-defensin (DEFB1; 602056). </p><p>Park et al. (2001) detected antibacterial and antifungal activity by HAMP, but in contrast to alpha-defensin (DEFA1; 125220), almost no toxicity against an erythroleukemia cell line. </p><p>Animal models (see later) indicate that the antimicrobial peptide hepcidin is probably a key regulator of iron absorption in mammals. The regulation of intestinal iron absorption is crucial to avoid toxicity. Disruption of this regulation in hereditary hemochromatosis (235200) leads to iron overload, cirrhosis, cardiomyopathy, arthritis, and endocrine failure (Roetto et al., 2003). The apparent lack of susceptibility to infections in individuals with inactivated HAMP genes suggests that the antimicrobial role of HAMP is not critical for staving off infection. </p><p>Most individuals with hereditary hemochromatosis (235200) are homozygous with respect to a missense mutation that disrupts the conformation of HFE (613609), an atypical HLA class I molecule. Mice lacking Hfe or producing an Hfe protein carrying the common C282Y mutation (613609.0001) develop hyperferremia and show high hepatic iron levels. In both humans and mice, hereditary hemochromatosis is associated with a paucity of iron in reticuloendothelial cells. Nicolas et al. (2003) crossed Hfe -/- mice with transgenic mice overexpressing Hamp and found that Hamp inhibited the iron accumulation normally observed in the Hfe -/- mice. It had been suggested that Hfe modulates uptake of transferrin-bound iron by undifferentiated intestinal crypt cells, thereby programming the absorptive capacity of enterocytes derived from these cells. Nicolas et al. (2003) proposed that their findings argued against the crypt programming model and suggested that failure of Hamp induction contributes to the pathogenesis of hemochromatosis, providing a rationale for the use of HAMP in the treatment of this disease. </p><p>Muckenthaler et al. (2003) likewise focused attention away from an exclusive role for the intestine in hereditary hemochromatosis. HFE deficiency in intestinal crypt cells had been thought to cause intestinal iron deficiency and greater expression of iron transporters such as SLC11A2 (600523) and SLC40A1 (604653). Muckenthaler et al. (2003) performed microarray assays to study changes in duodenal and hepatic gene expression in Hfe-deficient mice. They found unexpected alterations in the expression of Slc39a1 (the mouse ortholog of SLC40A1) and duodenal cytochrome b (CYBRD1; 605745), which encode key iron transport proteins, and Hamp. They proposed that inappropriate regulatory cues from the liver underlie greater duodenal iron absorption, possibly involving the ferric reductase Cybrd1. </p><p>In studies using cultured hepatocytes and mice, Nemeth et al. (2004) demonstrated that interleukin-6 (IL6; 147620) is the main mediator of hepcidin increase in inflammation, but is not required in the regulation of hepcidin by iron. In humans, infusion of IL6 rapidly increased hepcidin excretion with a concomitant decrease in serum iron and transferrin saturation. Nemeth et al. (2004) concluded that IL6 is the necessary and sufficient cytokine for the induction of hepcidin during inflammation and that the IL6-hepcidin axis is responsible for the hypoferremia of inflammation. </p><p>Nemeth et al. (2004) reported that hepcidin bound to ferroportin (604653) in tissue culture cells. After binding, ferroportin was internalized and degraded, leading to decreased export of cellular iron. Nemeth et al. (2004) postulated that the posttranslational regulation of ferroportin by hepcidin may complete a homeostatic loop regulating iron plasma levels and the tissue distribution of iron. </p><p>Robson et al. (2004) reviewed the relationship between hemochromatosis and iron homeostasis in general and in host defenses. They noted that hepcidin is an acute phase protein and HFE is a major histocompatibility complex (MHC) class I-like molecule, which suggests that other players in a novel pathway of iron metabolism may be involved in a host defense pathway that limits iron availability and restricts growth of invading pathogens. The authors reviewed the evidence that the regulation of iron homeostasis and the inflammatory and immune responses are linked in a highly complex interactive system, many facets of which must have come under intense evolutionary pressure and therefore may show broad homology over many species. They are likely to exhibit wide genetic heterogeneity paralleled by variability of response to infection among different ethnic groups. </p><p>Lee et al. (2005) showed that primary mouse hepatocytes could be stimulated by the cytokines IL6 (147620), IL1A (147760), and IL1B (147720) to express hepcidin message. IL10 (124092) had little to no stimulatory effect, and IFNB (147640) inhibited hepcidin transcription. </p><p>Tanno et al. (2007) hypothesized that accumulation of iron in the absence of blood transfusions in thalassemia patients may result from inappropriate suppression of the iron-regulating peptide hepcidin by an erythropoietic mechanism. To test this hypothesis, Tanno et al. (2007) examined erythroblast transcriptome profiles from 15 healthy nonthalassemic donors. Growth differentiation factor-15 (GDF15; 605312) showed increased expression and secretion during erythroblast maturation. Healthy volunteers had mean GDF15 serum concentrations of 450 +/- 50 pg/ml. In comparison, individuals with beta-thalassemia syndromes had elevated GDF15 serum levels (mean 66,000 +/- 9,600 pg/ml; range 4,800-248,000 pg/ml; P less than 0.05) that were positively correlated with the levels of soluble transferrin receptor (190010), erythropoietin (133170), and ferritin (see 134790). Serum from thalassemia patients suppressed hepcidin mRNA expression in primary human hepatocytes, and depletion of GDF15 reversed hepcidin suppression. Tanno et al. (2007) concluded that GDF15 overexpression arising from an expanded erythroid compartment contributes to iron overload in thalassemia syndromes by inhibiting hepcidin expression. </p><p>Du et al. (2008) identified TMPRSS6 (609862) as an essential component of a pathway that detects iron deficiency and blocks HAMP transcription, permitting enhanced dietary iron absorption. </p><p>Weizer-Stern et al. (2007) identified a putative p53 (TP53; 191170) response element in the HAMP promoter. Using chromatin immunoprecipitation, reporter assays, and a temperature-sensitive p53 cell line, they demonstrated that p53 bound and activated the HAMP promoter. Activation of p53 increased HAMP expression, while silencing p53 decreased HAMP expression in human hepatoma cells. Weizer-Stern et al. (2007) concluded that HAMP is a p53 target gene and suggested that iron deprivation via HAMP upregulation may be part of the p53-dependent defense mechanism against cancer. </p><p>Hepcidin is a key regulator of intestinal iron absorption whose expression is controlled by the bone morphogenetic protein (BMP; see 112264) and SMAD (see 601595) signaling pathway. Kautz et al. (2008) performed a genomic screen in mice fed either an iron-enriched or iron-deficient diet, which demonstrated that in contrast to other BMP genes, Bmp6 mRNA expression was regulated by iron similar to Hamp mRNA expression, and suggested that BMP6 has a preponderant role in the activation of the SMAD signaling pathway leading to hepcidin synthesis in vivo. </p><p>Hemojuvelin (HJV; 608374) is a coreceptor for BMPs, and inhibition of endogenous BMP signaling reduces hepcidin expression and increases serum iron in mice (Babitt et al. (2006, 2007)). Using a protein pull-down assay, Andriopoulos et al. (2009) demonstrated a direct physical interaction between recombinant soluble human HJV and BMP6. Intraperitoneal injection of BMP6 in mice caused increased hepatic hepcidin mRNA expression and reduced serum iron and transferrin (190000) saturation in a dose-dependent manner. Conversely, inhibition of endogenous Bmp6 in mice reduced hepcidin expression and increased serum iron. Andriopoulos et al. (2009) concluded that BMP6 is an HJV ligand and an endogenous regulator of hepcidin expression and iron metabolism. </p><p>Vecchi et al. (2009) found that hepatic hepcidin gene expression was induced by endoplasmic reticulum (ER) stress in tunicamycin-treated mice. Mice with ER stress developed hypoferremia and sequestration of iron in macrophages, most prominent in the spleen. In vitro cellular studies showed that the HAMP promoter was activated by CREBH (611998). Crebh-null mice did not demonstrate increased Hamp activity in response to ER stress. The findings linked the intracellular response involved in protein quality control to innate immunity and iron homeostasis. </p><p>Using mass spectrometry, Peslova et al. (2009) showed that hepcidin in human plasma or serum was bound by albumin (ALB; 103600) and by alpha-2-macroglobulin (A2M; 103950). Binding of hepcidin to albumin was nonspecific and displayed nonsaturable kinetics. However, binding of hepcidin to A2M was specific. Scatchard analysis estimated 2 hepcidin-binding sites per inactive A2M molecule. Proteolytic activation of A2M resulted in a sigmoidal binding curve, suggesting high-affinity cooperative allosteric binding of 4 hepcidin molecules per active A2M molecule. The hepcidin-A2M complex, but not the hepcidin-albumin complex, decreased ferroportin expression in J774 murine macrophages more effectively than hepcidin alone. Peslova et al. (2009) hypothesized that A2M has a role in regulating hepcidin action by sequestration and subsequent release. </p><p>Smith et al. (2013) showed that Il22 (605330), independent of Il6, could induce hepcidin production in mice, with a subsequent decrease in circulating serum iron and hemoglobin levels and a concomitant increase in splenic iron accumulation. This response was attenuated in the presence of the Il22r (IL22RA1; 605457)-associated signaling kinase, Tyk2 (176941). Antibody blockade of hepcidin partially reversed the effects on iron biology caused by Il22r stimulation. Smith et al. (2013) proposed that IL22 is involved in regulating hepcidin production and iron homeostasis. </p><p>Bessman et al. (2020) found that hepcidin is required for tissue repair in the mouse intestine after experimental damage. This effect was independent of hepatocyte-derived hepcidin or systemic iron levels. Rather, Bessman et al. (2020) found that conventional dendritic cells (cDCs) were the source of hepcidin that is induced by microbial stimulation in mice and is also prominent in the inflamed intestine of humans, and essential for tissue repair. cDC-derived hepcidin acted on ferroportin (SLC40A1; 604653)-expressing phagocytes to promote local iron sequestration, which regulated the microbiota and consequently facilitated intestinal repair. Bessman et al. (2020) concluded that their results identified a pathway whereby cDC-derived hepcidin promotes mucosal healing in the intestine through means of nutritional immunity. </p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Roetto et al. (2003) focused on the HAMP gene as the possible site of the defect in a form of juvenile hereditary hemochromatosis that was not linked to 1q (HFE2B; 613313). Using microsatellite markers encompassing a region of 2.7 cM on 19q13 in one family, they identified a region of homozygosity in both probands. They then sequenced the HAMP coding region, exon-intron boundaries, and 5- and 3-prime untranslated regions in this family and a second family and identified 2 mutations (606464.0001, 606464.0002). </p><p>Merryweather-Clarke et al. (2003) described 2 families who exhibited digenic inheritance of hemochromatosis. In family A, the proband had a juvenile hemochromatosis (613313) phenotype and was heterozygous for the C282Y mutation in the HFE gene (613609.0001) as well as a HAMP frameshift mutation (606464.0003). The proband's unaffected mother was also heterozygous for the HAMP frameshift mutation, but lacked the HFE C282Y mutation and was heterozygous for the HFE H63D mutation (613609.0002). In family B, there was a correlation between severity of iron overload, heterozygosity for a HAMP G71D mutation (606464.0004), and heterozygosity or homozygosity for the HFE C282Y mutation. The authors proposed that the phenotype of C282Y heterozygotes and homozygotes may be modified by heterozygosity for mutations which disrupt the function of hepcidin in iron homeostasis, with the severity of iron overload corresponding to the severity of the HAMP mutation. </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 (604720)-, HFE2 (608374)-, and HAMP-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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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Nicolas et al. (2001) found that hepcidin gene expression was totally inhibited in mice exhibiting iron overload consequent to targeted disruption of the Usf2 gene. In these Usf2 knockout mice, the development of iron overload was strikingly similar to that observed in human hereditary hemochromatosis and in mice with knockout of the Hfe gene (613609), the mouse model of hemochromatosis; iron accumulated in parenchymal cells (in particular, liver and pancreas), whereas the reticuloendothelial system was spared from this iron loading. Nicolas et al. (2001) suggested that this phenotypic trait could be attributed to the absence of hepcidin in the Usf2 knockout mice. They conjectured that the reverse situation, namely overexpression of hepcidin, might result in phenotypic traits of iron deficiency. Nicolas et al. (2002) addressed this question by generating transgenic mice expressing hepcidin under the control of the liver-specific transthyretin (TTR; 176300) promoter. They found that most of the transgenic mice were born with pale skin and died within a few hours after birth. The animals had decreased body iron levels and presented severe microcytic hypochromic anemia. Three mosaic transgenic animals that survived were unequivocally identified by physical features, including reduced body size, pallor, and hairless and crumpled skin. These pleiotropic effects were found to be associated with erythrocyte abnormalities, with marked anisocytosis, poikilocytosis, and hypochromia, which are features of iron-deficiency anemia. These results supported the proposed role of hepcidin as an iron-regulatory hormone. </p><p>In contrast to the human genome, which contains only 1 copy of the hepcidin gene, the mouse genome contains 2 highly similar hepcidin genes, Hepc1 and Hepc2, which are, however, considerably divergent at the level of the corresponding mature 25-amino acid peptide. Nicolas et al. (2002) established the role of hepcidin in iron metabolism by generating transgenic mice overexpressing Hepc1 in the liver. A severe iron-deficient anemia phenotype resulted. Lou et al. (2004) reported that, in contrast to the Hepc1 transgenic mice, none of the Hepc2 transgenic animals suffered from anemia. They all developed normally with hematologic parameters similar to the nontransgenic littermates. Hepc2 transgenic mRNA levels were found to be very high for all lines, compared with the level of Hepc1 transgene mRNA necessary to produce severe anemia. These data provided evidence that Hepc2 does not act on iron metabolism like Hepc1 and gave clues for the identification of amino acids important for the iron-regulatory action of the mature 25-amino acid peptide. </p><p>Rivera et al. (2005) found that treatment with human hepcidin induced acute hypoferremia in mice, demonstrating the bioactivity of human hepcidin in mice. To investigate the chronic effects of hepcidin, the authors designed tumor xenografts expressing high levels of human hepcidin in mice. Mice with hepcidin-producing tumors developed anemia even when maintained on a high-iron diet. Furthermore, liver iron stores were significantly increased by hepcidin, and iron was present predominantly in hepatocytes. </p><p>Ramey et al. (2007) found that Hepc1 -/- mice accumulated iron in exocrine pancreas. Iron overload in exocrine pancreas did not affect production and secretion of insulin. Furthermore, glucose homeostasis was not impaired, whole body insulin sensitivity was preserved, and Hepc1 -/- mice did not develop insulin resistance. </p><p>Iron excess is regulated through a pathway involving hemojuvelin that stimulates expression of hepcidin, whereas iron attenuation is countered through a pathway involving TMPRSS6 that suppresses expression of hepcidin. Truksa et al. (2009) found that double-knockout mice lacking both Tmprss6 and hemojuvelin exhibited low hepcidin expression and iron overload. However, double-knockout mice showed lower levels of iron in heart than hemojuvelin -/- mice, demonstrating a possible cardioprotective effect resulting from loss of Tmprss6. This phenotype supported a model in which hemojuvelin is a major substrate for Tmprss6 protease activity. </p><p>Malerba et al. (2020) found that hepcidin production was induced in skin of patients with group A Streptococcus (GAS) necrotizing fasciitis (NF), as well as in GAS-infected skin of mice, especially in keratinocytes. Keratinocyte-specific hepcidin deficiency failed to restrict systemic spread of GAS infection from an initial tissue focus into bloodstream and systemic organs of mice. However, hepcidin did not have a direct antimicrobial effect on bacteria, but instead promoted production of Cxcl1 (155730) in keratinocytes, resulting in neutrophil recruitment. Unlike Cxcl1, hepcidin was resistant to degradation by major GAS proteases, suggesting it could be used to promote production of Cxcl1 or maintain steady-state levels of Cxcl1 in infected tissue. Indeed, injection of hepcidin at the infection site limited or prevented systemic spread of GAS infection in mice, suggesting that hepcidin agonists may have a therapeutic role in NF. </p>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>5 Selected Examples):</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>.0001 HEMOCHROMATOSIS, TYPE 2B</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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HAMP, 1-BP DEL, 93G
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<br />
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SNP: rs1189025914,
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ClinVar: RCV000004504
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<span class="mim-text-font">
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<p>In 2 affected sisters, the offspring of third cousins, with juvenile hemochromatosis (HFE2B; 613313), Roetto et al. (2003) found deletion of a guanine in exon 2 at position 93 of the HAMP cDNA (93delG). The sisters were homozygous with respect to this deletion, and both parents were heterozygous. The deletion resulted in a frameshift, and, if mutated RNA achieved translation, generated an elongated (179 residues) abnormal prohepcidin peptide (in contrast to the normal propeptide of 84 amino acids). </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 HEMOCHROMATOSIS, TYPE 2B</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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HAMP, ARG56TER
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<br />
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SNP: rs104894695,
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ClinVar: RCV000004505
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a family with juvenile hereditary hemochromatosis (HFE2B; 613313), Roetto et al. (2003) found a C-to-T transition at position 166 in exon 3 of HAMP cDNA (166C-T), which changed arginine at position 56 to a stop codon (R56X). The R56X amino acid change occurred in a pentaarginine (residues 55-59) basic domain, which is thought to be the recognition site for pro-hormone convertases, and produces a truncated prohepcidin lacking all mature peptide sequences. </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, JUVENILE, DIGENIC</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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HAMP, 4-BP DEL, ATGG
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<br />
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SNP: rs1422879641,
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ClinVar: RCV000004506
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Merryweather-Clarke et al. (2003) reported an individual with a juvenile hemochromatosis (613313) phenotype who was heterozygous for the C282Y mutation in the HFE gene (613609.0001) as well as a 4-bp HAMP frameshift mutation. The mutation deleted the last codon of exon 2 (met50) as well as the first base of the splice donor site of intron 2 (IVS+1(-G)). The mutation was predicted to result in retention of the splice consensus site, but altered the reading frame, extending it beyond the end of the normal transcript. The proband's unaffected mother was also heterozygous for the HAMP frameshift mutation, but lacked the HFE C282Y mutation and was heterozygous for the HFE H63D mutation (613609.0002). </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 2A, 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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HAMP, GLY71ASP
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<br />
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SNP: rs104894696,
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gnomAD: rs104894696,
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ClinVar: RCV000004507, RCV000599701, RCV000990194, RCV001086432, RCV001127434, RCV003974795
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Merryweather-Clarke et al. (2003) reported a 2-generation family with juvenile hemochromatosis (602390) in which the proband and his sister were homozygous for a C282Y mutation in HFE (253200.0001) and heterozygous for a gly71-to-asp (G71D) mutation in the HAMP gene. The father was heterozygous for both HFE C282Y and HAMP G71D. There was a correlation between severity of iron overload, heterozygosity for HAMP G71D, and heterozygosity or homozygosity for the HFE C282Y mutation. </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>.0005 HEMOCHROMATOSIS, TYPE 2B</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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HAMP, +14G-A, 5-PRIME UTR
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<br />
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SNP: rs944843686,
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gnomAD: rs944843686,
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ClinVar: RCV000004508, RCV003588556
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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 29-year-old Portuguese man with juvenile hemochromatosis (602390), Matthes et al. (2004) identified a homozygous G-to-A transition at position +14 of the 5-prime UTR relative to the cap site of the mRNA for HAMP. The mutation created a new initiation codon at position +14 of the 5-prime UTR, which induced a shift of the reading frame and the generation of an abnormal protein. This protein was probably unstable or otherwise degraded, as it was not found on bidirectional protein gel electrophoresis. The patient was diagnosed with insulin-dependent diabetes mellitus and severe heart failure; he exhibited skin hyperpigmentation, hepatosplenomegaly, and hypogonadism. The patient's 24-year-old sister was homozygous for the same mutation, whereas both parents and a cousin were found to be heterozygous, with no signs of iron overload. The sister had no clinical findings, but laboratory tests showed increased transaminases and iron overload. Liver biopsy showed moderate, predominantly periportal, hepatocellular siderosis without cirrhosis. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>REFERENCES</strong>
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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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|
Andriopoulos, B., Jr., Corradini, E., Xia, Y., Faasse, S. A., Chen, S., Grgurevic, L., Knutson, M. D., Pietrangelo, A., Vukicevic, S., Lin, H. Y., Babitt, J. L.
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<strong>BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism.</strong>
|
|
Nature Genet. 41: 482-487, 2009.
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[PubMed: 19252486]
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[Full Text: https://doi.org/10.1038/ng.335]
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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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|
Babitt, J. L., Huang, F. W., Wrighting, D. M., Xia, Y., Sidis, Y., Samad, T. A., Campagna, J. A., Chung, R. T., Schneyer, A. L., Woolf, C. J., Andrews, N. C., Lin, H. Y.
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<strong>Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression.</strong>
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Nature Genet. 38: 531-539, 2006.
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[PubMed: 16604073]
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[Full Text: https://doi.org/10.1038/ng1777]
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<li>
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<p class="mim-text-font">
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Babitt, J. L., Huang, F. W., Xia, Y., Sidis, Y., Andrews, N. C., Lin, H. Y.
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<strong>Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance.</strong>
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J. Clin. Invest. 117: 1933-1939, 2007.
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[PubMed: 17607365]
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[Full Text: https://doi.org/10.1172/JCI31342]
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<li>
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<p class="mim-text-font">
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|
Bessman, N. J., Mathieu, J. R. R., Renassia, C., Zhou, L., Fung, T. C., Fernandez, K. C., Austin, C., Moeller, J. B., Zumerle, S., Louis, S., Vaulont, S., Ajami, N. J., and 9 others.
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<strong>Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing.</strong>
|
|
Science 368: 186-189, 2020.
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[PubMed: 32273468]
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[Full Text: https://doi.org/10.1126/science.aau6481]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Du, X., She, E., Gelbart, T., Truksa, J., Lee, P., Xia, Y., Khovananth, K., Mudd, S., Mann, N., Moresco, E. M. Y., Beutler, E., Beutler, B.
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<strong>The serine protease TMPRSS6 is required to sense iron deficiency.</strong>
|
|
Science 320: 1088-1092, 2008.
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[PubMed: 18451267]
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[Full Text: https://doi.org/10.1126/science.1157121]
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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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Kautz, L., Meynard, D., Monnier, A., Darnaud, V., Bouvet, R., Wang, R. H., Deng, C., Vaulont, S., Mosser, J., Coppin, H., Roth, M. P.
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<strong>Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver.</strong>
|
|
Blood 112: 1503-1509, 2008.
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|
|
[PubMed: 18539898]
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[Full Text: https://doi.org/10.1182/blood-2008-03-143354]
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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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Krause, A., Neitz, S., Magert, H.-J., Schulz, A., Forssmann, W.-G., Schulz-Knappe, P., Adermann, K.
|
|
<strong>LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity.</strong>
|
|
FEBS Lett. 480: 147-150, 2000.
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|
|
[PubMed: 11034317]
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[Full Text: https://doi.org/10.1016/s0014-5793(00)01920-7]
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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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Lee, P., Peng, H., Gelbart, T., Wang, L., Beutler, E.
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<strong>Regulation of hepcidin transcription by interleukin-1 and interleukin-6.</strong>
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Proc. Nat. Acad. Sci. 102: 1906-1910, 2005.
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[PubMed: 15684062]
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[Full Text: https://doi.org/10.1073/pnas.0409808102]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Lou, D.-Q., Nicolas, G., Lesbordes, J.-C., Viatte, L., Grimber, G., Szajnert, M.-F., Kahn, A., Vaulont, S.
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|
<strong>Functional differences between hepcidin 1 and 2 in transgenic mice.</strong>
|
|
Blood 103: 2816-2821, 2004.
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|
[PubMed: 14604961]
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|
|
[Full Text: https://doi.org/10.1182/blood-2003-07-2524]
|
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|
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Malerba, M., Louis, S., Cuvellier, S., Shambat, S. M., Hua, C., Gomart, C., Fouet, A., Ortonne, N., Decousser, J.-W., Zinkernagel, A. S., Mathieu, J. R. R., Peyssonnaux, C.
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<strong>Epidermal hepcidin is required for neutrophil response to bacterial infection.</strong>
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J. Clin. Invest. 130: 329-334, 2020.
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[PubMed: 31600168]
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[Full Text: https://doi.org/10.1172/JCI126645]
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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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Matthes, T., Aguilar-Martinez, P., Pizzi-Bosman, L., Darbellay, R., Rubbia-Brandt, L., Giostra, E., Michel, M., Ganz, T., Beris, P.
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<strong>Severe hemochromatosis in a Portuguese family associated with a new mutation in the 5-prime-UTR of the HAMP gene.</strong>
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|
Blood 104: 2181-2183, 2004.
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[PubMed: 15198949]
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[Full Text: https://doi.org/10.1182/blood-2004-01-0332]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Merryweather-Clarke, A. T., Cadet, E., Bomford, A., Capron, D., Viprakasi, V., Miller, A., McHugh, P. J. Chapman, R. W., Pointon, J. J., Wimhurst, V. L. C., Livesey, K. J., Tanphaichitr, V., Rochette, J., Robson, K. J. H.
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<strong>Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis.</strong>
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Hum. Molec. Genet. 12: 2241-2247, 2003.
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[PubMed: 12915468]
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[Full Text: https://doi.org/10.1093/hmg/ddg225]
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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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|
Muckenthaler, M., Roy, C. N., Custodio, A. O., Minana, B., deGraaf, J., Montross, L. K., Andrews, N. C., Hentze, M. W.
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<strong>Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis.</strong>
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|
Nature Genet. 34: 102-107, 2003.
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[PubMed: 12704390]
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[Full Text: https://doi.org/10.1038/ng1152]
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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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|
Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B. K., Ganz, T.
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<strong>IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin.</strong>
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J. Clin. Invest. 113: 1271-1276, 2004.
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[PubMed: 15124018]
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[Full Text: https://doi.org/10.1172/JCI20945]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Nemeth, E., Tuttle, M. S., Powelson, J., Vaughn, M. B., Donovan, A., Ward, D. M., Ganz, T., Kaplan, J.
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|
<strong>Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.</strong>
|
|
Science 306: 2090-2093, 2004.
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[PubMed: 15514116]
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[Full Text: https://doi.org/10.1126/science.1104742]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Nicolas, G., Bennoun, M., Devaux, I., Beaumont, C., Grandchamp, B., Kahn, A., Vaulont, S.
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|
<strong>Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice.</strong>
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Proc. Nat. Acad. Sci. 98: 8780-8785, 2001.
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[PubMed: 11447267]
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[Full Text: https://doi.org/10.1073/pnas.151179498]
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|
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Nicolas, G., Bennoun, M., Porteu, A., Mativet, S., Beaumont, C., Grandchamp, B., Sirito, M., Sawadogo, M., Kahn, A., Vaulont, S.
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|
<strong>Severe iron deficiency anemia in transgenic mice expressing liver hepcidin.</strong>
|
|
Proc. Nat. Acad. Sci. 99: 4596-4601, 2002.
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|
[PubMed: 11930010]
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[Full Text: https://doi.org/10.1073/pnas.072632499]
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|
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|
|
</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Nicolas, G., Viatte, L., Lou, D.-Q., Bennoun, M., Beaumont, C., Kahn, A., Andrews, N. C., Vaulont, S.
|
|
<strong>Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis.</strong>
|
|
Nature Genet. 34: 97-101, 2003.
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|
|
|
|
|
[PubMed: 12704388]
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|
|
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|
|
[Full Text: https://doi.org/10.1038/ng1150]
|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Park, C. H., Valore, E. V., Waring, A. J., Ganz, T.
|
|
<strong>Hepcidin, a urinary antimicrobial peptide synthesized in the liver.</strong>
|
|
J. Biol. Chem. 276: 7806-7810, 2001.
|
|
|
|
|
|
[PubMed: 11113131]
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|
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|
|
[Full Text: https://doi.org/10.1074/jbc.M008922200]
|
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|
|
</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Peslova, G., Petrak, J., Kuzelova, K., Hrdy, I., Halada, P., Kuchel, P. W., Soe-Lin, S., Ponka, P., Sutak, R., Becker, E., Huang, M. L.-H., Rahmanto, Y. S., Richardson, D. R., Vyoral, D.
|
|
<strong>Hepcidin, the hormone of iron metabolism, is bound specifically to alpha-2-macroglobulin in blood.</strong>
|
|
Blood 113: 6225-6236, 2009.
|
|
|
|
|
|
[PubMed: 19380872]
|
|
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|
|
[Full Text: https://doi.org/10.1182/blood-2009-01-201590]
|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Pigeon, C., Ilyin, G., Courselaud, B., Leroyer, P., Turlin, B., Brissot, P., Loreal, O.
|
|
<strong>A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload.</strong>
|
|
J. Biol. Chem. 276: 7811-7819, 2001.
|
|
|
|
|
|
[PubMed: 11113132]
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|
|
[Full Text: https://doi.org/10.1074/jbc.M008923200]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Ramey, G., Faye, A., Durel, B., Viollet, B., Vaulont, S.
|
|
<strong>Iron overload in Hepc1-/- mice is not impairing glucose homeostasis.</strong>
|
|
FEBS Lett. 581: 1053-1057, 2007.
|
|
|
|
|
|
[PubMed: 17316628]
|
|
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|
|
[Full Text: https://doi.org/10.1016/j.febslet.2007.02.002]
|
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</p>
|
|
</li>
|
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<li>
|
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<p class="mim-text-font">
|
|
Rivera, S., Liu, L., Nemeth, E., Gabayan, V., Sorensen, O. E., Ganz, T.
|
|
<strong>Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia.</strong>
|
|
Blood 105: 1797-1802, 2005.
|
|
|
|
|
|
[PubMed: 15479721]
|
|
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|
|
[Full Text: https://doi.org/10.1182/blood-2004-08-3375]
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Robson, K. J. H., Merryweather-Clarke, A. T., Cadet, E., Viprakasit, V., Zaahl, M. G., Pointon, J. J., Weatherall, D. J., Rochette, J.
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Roetto, A., Papanikolaou, G., Politou, M., Alberti, F., Girelli, D., Christakis, J., Loukopoulos, D., Camaschella, C.
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<strong>Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis.</strong>
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Smith, C. L., Arvedson, T. L., Cooke, K. S., Dickmann, L. J., Forte, C., Li, H., Merriam, K. L., Perry, V. K., Tran, L., Rottman, J. B., Maxwell, J. R.
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Matthew B. Gross - updated : 01/06/2021<br>Bao Lige - updated : 01/06/2021<br>Ada Hamosh - updated : 04/28/2020<br>Ada Hamosh - updated : 10/23/2018<br>Paul J. Converse - updated : 8/13/2014<br>Patricia A. Hartz - updated : 11/2/2010<br>Cassandra L. Kniffin - updated : 8/24/2009<br>Patricia A. Hartz - updated : 4/23/2009<br>Patricia A. Hartz - updated : 7/11/2008<br>Ada Hamosh - updated : 6/10/2008<br>Ada Hamosh - updated : 3/26/2008<br>Patricia A. Hartz - updated : 6/7/2005<br>Victor A. McKusick - updated : 2/17/2005<br>Ada Hamosh - updated : 1/27/2005<br>Victor A. McKusick - updated : 12/20/2004<br>Victor A. McKusick - updated : 8/23/2004<br>Marla J. F. O'Neill - updated : 7/1/2004<br>Victor A. McKusick - updated : 1/2/2004<br>George E. Tiller - updated : 11/13/2003<br>Victor A. McKusick - updated : 4/18/2003<br>Victor A. McKusick - updated : 12/10/2002<br>Victor A. McKusick - updated : 9/23/2002
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