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Entry
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- *612386 - FERROCHELATASE; FECH
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- OMIM
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<div class="container hidden-print">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*612386</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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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>
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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="#evolution">Evolution</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="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/612386">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000066926;t=ENST00000262093" 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=2235" 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=612386" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000066926;t=ENST00000262093" 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_000140,NM_001012515,NM_001371094,NM_001371095,NM_001374778,XM_011525881" 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_000140" 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=612386" 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=01509&isoform_id=01509_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/FECH" 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/219656,758655,4378984,6706213,20269851,20269852,21751005,33096717,37572293,54696778,54696780,60499021,60499025,62897941,85701348,119583450,119583451,158259335,194389098,767998426,1694437564,1694437629,1764714895,2462559781" 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/P22830" 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=2235" 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=ENSG00000066926;t=ENST00000262093" 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=FECH" 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=FECH" 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+2235" 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/FECH" 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:2235" 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/2235" 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=chr18&hgg_gene=ENST00000262093.11&hgg_start=57544377&hgg_end=57586702&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:3647" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/fech" 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=612386[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=612386[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/ENSG00000066926" 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=FECH" 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=FECH" 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=FECH" 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=FECH&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/PA28087" 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:3647" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0266268.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:95513" 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/FECH#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:95513" 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/2235/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://omia.org/OMIA000836/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2235" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00010645;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-000928-1" 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:2235" 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=FECH&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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612386
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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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FERROCHELATASE; FECH
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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">
|
|
HEME SYNTHASE<br />
|
|
HEME SYNTHETASE<br />
|
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IRON CHELATASE
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=FECH" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FECH</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/18/206?start=-3&limit=10&highlight=206">18q21.31</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr18:57544377-57586702&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'})">18:57,544,377-57,586,702</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">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/18/206?start=-3&limit=10&highlight=206">
|
|
18q21.31
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Protoporphyria, erythropoietic, 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/177000"> 177000 </a>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/612386" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/612386" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
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<p>Ferrochelatase (FECH; <a href="https://enzyme.expasy.org/EC/4.99.1.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 4.99.1.1</a>), the terminal enzyme of the heme biosynthetic pathway, catalyzes the insertion of iron into protoporphyrin to form heme.</p>
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<p>By screening a human placenta cDNA library with a radiolabeled fragment of mouse Fech cDNA, <a href="#15" class="mim-tip-reference" title="Nakahashi, Y. N., Taketani, S. T., Okuda, M. O., Inoue, K. I., Tokunaga, R. T. <strong>Molecular cloning and sequence analysis of cDNA encoding human ferrochelatase.</strong> Biochem. Biophys. Res. Commun. 173: 748-755, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2260980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2260980</a>] [<a href="https://doi.org/10.1016/s0006-291x(05)80099-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2260980">Nakahashi et al. (1990)</a> cloned a cDNA for human ferrochelatase. The deduced protein contains 423 amino acids and has a molecular mass of about 48 kD. Sequence analysis showed that the mature protein has 369 amino acids with a putative leader sequence of 54 amino acids and a molecular mass of about 42 kD. The human and mouse enzymes share 88% sequence identity. Northern blot analysis detected 2 mRNAs of 2.5 and 1.6 kb in K562 and HepG2 cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2260980" 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="Gouya, L., Martin-Schmitt, C., Robreau, A.-M., Austerlitz, F., Da Silva, V., Brun, P., Simonin, S., Lyoumi, S., Grandchamp, B., Beaumont, C., Puy, H., Deybach, J.-C. <strong>Contribution of a common single-nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria.</strong> Am. J. Hum. Genet. 78: 2-14, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16385445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16385445</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16385445[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/10.1086/498620" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16385445">Gouya et al. (2006)</a> estimated the neutrality of sequence differences found between human and chimpanzee FECH genes, by calculating the ratio of nonsynonymous to synonymous mutations. Restricting their calculations to the coding region for the mature part of the protein, they found strong evidence of negative Darwinian selection of the mutant altering the function of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16385445" 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="#27" class="mim-tip-reference" title="Whitcombe, D. M., Carter, N. P., Albertson, D. G., Smith, S. J., Rhodes, D. A., Cox, T. M. <strong>Assignment of the human ferrochelatase gene (FECH) and a locus for protoporphyria to chromosome 18q22.</strong> Genomics 11: 1152-1154, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1783383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1783383</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90044-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1783383">Whitcombe et al. (1991)</a> mapped the FECH gene to chromosome 18 by hybridization of cDNA to sorted chromosomes. Subchromosomal localization to 18q22 was achieved by in situ hybridization. By means of fluorescence in situ hybridization (FISH), <a href="#11" class="mim-tip-reference" title="Inazawa, J., Taketani, S., Nakagawa, H., Inoue, K., Misawa, S., Abe, T. <strong>Assignment of the human ferrochelatase gene (FCE) to chromosome 18 at region q21.3. (Abstract)</strong> Cytogenet. Cell Genet. 58: 2014, 1991."None>Inazawa et al. (1991)</a> demonstrated that the FECH gene is located on band 18q21.3. <a href="#6" class="mim-tip-reference" title="Brenner, D. A., Didier, J. M., Frasier, F., Christensen, S. R., Evans, G. A., Dailey, H. A. <strong>A molecular defect in human protoporphyria.</strong> Am. J. Hum. Genet. 50: 1203-1210, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1376018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1376018</a>]" pmid="1376018">Brenner et al. (1992)</a> mapped the FECH gene to 18q21.3 by chromosomal in situ suppression hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1783383+1376018" 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="Taketani, S., Inazawa, J., Nakahashi, Y., Abe, T., Tokunaga, R. <strong>Structure of the human ferrochelatase gene: exon/intron gene organization and location of the gene to chromosome 18.</strong> Europ. J. Biochem. 205: 217-222, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1555582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1555582</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1992.tb16771.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1555582">Taketani et al. (1992)</a> demonstrated that the FECH gene contains 11 exons and has a minimum size of about 45 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1555582" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In patients with erythropoietic porphyria (EPP; <a href="/entry/177000">177000</a>), <a href="#5" class="mim-tip-reference" title="Bonkowsky, H. L., Bloomer, J. R., Ebert, P. S., Mahoney, M. J. <strong>Heme synthetase deficiency in human protoporphyria: demonstration of the defect in liver and cultured skin fibroblasts.</strong> J. Clin. Invest. 56: 1139-1148, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1184741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1184741</a>] [<a href="https://doi.org/10.1172/JCI108189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1184741">Bonkowsky et al. (1975)</a> and <a href="#3" class="mim-tip-reference" title="Bloomer, J. R. <strong>Characterization of deficient heme synthase activity in protoporphyria with cultured skin fibroblasts.</strong> J. Clin. Invest. 65: 321-328, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7356682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7356682</a>] [<a href="https://doi.org/10.1172/JCI109675" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7356682">Bloomer (1980)</a> demonstrated reduction in activity of ferrochelatase to 10 to 25% of normal levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7356682+1184741" 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="Sellers, V. M., Dailey, T. A., Dailey, H. A. <strong>Examination of ferrochelatase mutations that cause erythropoietic protoporphyria.</strong> Blood 91: 3980-3985, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9573038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9573038</a>]" pmid="9573038">Sellers et al. (1998)</a> engineered recombinant human ferrochelatase to have individual exon deletions corresponding to exons 3 through 11. When expressed in E. coli, none of these possessed significant enzyme activity and all lacked the 2Fe-2S cluster. One of the human missense mutations, F417S (<a href="#0004">612386.0004</a>), and a series of amino acid replacements at this site (i.e., F417W, F417Y, and F417L) were found, with the exception of F417L, to lack enzyme activity and did not contain the 2Fe-2S cluster in vivo or as isolated in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9573038" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Ohgari, Y., Sawamoto, M., Yamamoto, M., Kohno, H., Taketani, S. <strong>Ferrochelatase consisting of wild-type and mutated subunits from patients with a dominant-inherited disease, erythropoietic protoporphyria, is an active but unstable dimer.</strong> Hum. Molec. Genet. 14: 327-334, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15574461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15574461</a>] [<a href="https://doi.org/10.1093/hmg/ddi029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15574461">Ohgari et al. (2005)</a> coexpressed human ferrochelatase carrying His- and HA-tags in a tandem fashion in E. coli and found that ferrochelatase formed a homodimer. Homodimers of missense-mutated enzyme were produced in small amounts and showed very low activity. Heterodimers with wildtype and missense-mutated enzyme had reduced, but significant, enzymatic activity without a marked change of Km values for substrates. Heat treatment led to a rapid inactivation of the heterodimeric mutants, indicating instability. <a href="#16" class="mim-tip-reference" title="Ohgari, Y., Sawamoto, M., Yamamoto, M., Kohno, H., Taketani, S. <strong>Ferrochelatase consisting of wild-type and mutated subunits from patients with a dominant-inherited disease, erythropoietic protoporphyria, is an active but unstable dimer.</strong> Hum. Molec. Genet. 14: 327-334, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15574461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15574461</a>] [<a href="https://doi.org/10.1093/hmg/ddi029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15574461">Ohgari et al. (2005)</a> hypothesized that instability of the heterodimer containing normal and mutated ferrochelatase, as well as the low production levels due to the structural defect of the mutant protein, causes the weak enzymatic activity of ferrochelatase in EPP patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15574461" 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="#17" class="mim-tip-reference" title="Phillips, J., Farrell, C., Wang, Y., Singal, A. K., Anderson, K., Balwani, M., Bissell, M., Bonkovsky, H., Seay, T., Paw, B., Desnick, R., Bloomer, J. <strong>Strong correlation of ferrochelatase enzymatic activity with mitoferrin-1 mRNA in lymphoblasts of patients with protoporphyria.</strong> Molec. Genet. Metab. 128: 391-395, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30391163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30391163</a>] [<a href="https://doi.org/10.1016/j.ymgme.2018.10.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30391163">Phillips et al. (2019)</a> studied EBV-transformed lymphoblastoid cells from 10 individuals with X-linked erythropoietic protoporphyria (XLEPP; <a href="/entry/300752">300752</a>) and ALAS2 (<a href="/entry/301300">301300</a>) mutations, 20 individuals with erythropoietic protoporphyria-1 (EPP1; <a href="/entry/177000">177000</a>) with compound heterozygous FECH mutations (10 patients with the low-expression IVS3-48C-T splicing mutation (<a href="#0015">612386.0015</a>) and a cys422-to-gly substitution and 10 with the IVS3-48C-T splicing mutation and a nonsense or splicing null mutation), and 21 controls. <a href="#17" class="mim-tip-reference" title="Phillips, J., Farrell, C., Wang, Y., Singal, A. K., Anderson, K., Balwani, M., Bissell, M., Bonkovsky, H., Seay, T., Paw, B., Desnick, R., Bloomer, J. <strong>Strong correlation of ferrochelatase enzymatic activity with mitoferrin-1 mRNA in lymphoblasts of patients with protoporphyria.</strong> Molec. Genet. Metab. 128: 391-395, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30391163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30391163</a>] [<a href="https://doi.org/10.1016/j.ymgme.2018.10.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30391163">Phillips et al. (2019)</a> found that cells from all of the patients had reduced FECH enzyme activity compared with controls and that the decrease in FECH enzyme activity strongly correlated to MFRN1 (SLC25A37; <a href="/entry/610387">610387</a>) mRNA levels. <a href="#17" class="mim-tip-reference" title="Phillips, J., Farrell, C., Wang, Y., Singal, A. K., Anderson, K., Balwani, M., Bissell, M., Bonkovsky, H., Seay, T., Paw, B., Desnick, R., Bloomer, J. <strong>Strong correlation of ferrochelatase enzymatic activity with mitoferrin-1 mRNA in lymphoblasts of patients with protoporphyria.</strong> Molec. Genet. Metab. 128: 391-395, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30391163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30391163</a>] [<a href="https://doi.org/10.1016/j.ymgme.2018.10.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30391163">Phillips et al. (2019)</a> also found a reduction in mitochondrial iron levels in patients with EPP1 with FECH IVS3-48C-T/nonsense mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30391163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a patient with erythropoietic protoporphyria (EPP1; <a href="/entry/177000">177000</a>), <a href="#12" class="mim-tip-reference" title="Lamoril, J., Boulechfar, S., de Verneuil, H., Grandchamp, B., Nordmann, Y., Deybach, J.-C. <strong>Human erythropoietic protoporphyria: two point mutations in the ferrochelatase gene.</strong> Biochem. Biophys. Res. Commun. 181: 594-599, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1755842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1755842</a>] [<a href="https://doi.org/10.1016/0006-291x(91)91231-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1755842">Lamoril et al. (1991)</a> found compound heterozygosity for 2 mutations in the FECH gene (<a href="#0001">612386.0001</a>-<a href="#0002">612386.0002</a>). Each parent was heterozygous for one of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1755842" 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="Rufenacht, U. B., Gouya, L., Schneider-Yin, X., Puy, H., Schafer, B. W., Aquaron, R., Nordmann, Y., Minder, E. I., Deybach, J. C. <strong>Systematic analysis of molecular defects in the ferrochelatase gene from patients with erythropoietic protoporphyria.</strong> Am. J. Hum. Genet. 62: 1341-1352, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585598</a>] [<a href="https://doi.org/10.1086/301870" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9585598">Rufenacht et al. (1998)</a> conducted a systematic mutation analysis of the FECH gene, following a procedure that combines the exon-by-exon denaturing gradient gel electrophoresis screening of FECH genomic DNA and direct sequencing. They characterized 20 different mutations, 15 of which were described for the first time, in 26 of 29 EPP patients of Swiss and French origin. All the EPP patients, including those with liver complications, were heterozygous for the mutations identified in the FECH gene. The deleterious effect of all missense mutations was assessed by bacterial expression of the respective FECH cDNAs generated by site-directed mutagenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9585598" 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="#21" class="mim-tip-reference" title="Schneider-Yin, X., Gouya, L., Dorsey, M., Rufenacht, U., Deybach, J.-C., Ferreira, G. C. <strong>Mutations in the iron-sulfur cluster ligands of the human ferrochelatase lead to erythropoietic protoporphyria.</strong> Blood 96: 1545-1549, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10942404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10942404</a>]" pmid="10942404">Schneider-Yin et al. (2000)</a> identified 5 new mutations in patients with EPP. One was a triple point mutation (<a href="#0014">612386.0014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10942404" 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="Schneider-Yin, X., Gouya, L., Meier-Weinand, A., Deybach, J.-C., Minder, E. I. <strong>New insights into the pathogenesis of erythropoietic protoporphyria and their impact on patient care.</strong> Europ. J. Pediat. 159: 719-725, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11039124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11039124</a>] [<a href="https://doi.org/10.1007/s004310000494" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11039124">Schneider-Yin et al. (2000)</a> pointed out that the genetic constitution of a patient with overt EPP consists of a mutated FECH allele and a 'low expressed' normal allele; that of an asymptomatic carrier is a combination of a mutated and a normally expressed FECH allele. They stated that the identification of the 'low expressed' allele was facilitated by haplotype analysis using 2 single-nucleotide polymorphisms (SNPs): -251A-G in the promoter region and IVS1-23C-T. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11039124" 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 haplotype segregation analysis, <a href="#8" class="mim-tip-reference" title="Gouya, L., Puy, H., Robreau, A.-M., Bourgeois, M., Lamoril, J., Da Silva, V., Grandchamp, B., Deybach, J.-C. <strong>The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH.</strong> Nature Genet. 30: 27-28, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11753383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11753383</a>] [<a href="https://doi.org/10.1038/ng809" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11753383">Gouya et al. (2002)</a> showed that the mechanism for the low expression of FECH is an IVS3-48T-C polymorphism (<a href="#0015">612386.0015</a>) that modulates the use of a constitutive aberrant acceptor splice site. The aberrantly spliced mRNA is degraded by a nonsense-mediated decay mechanism, producing a decreased steady-state level of mRNA and the additional FECH enzyme deficiency necessary for EPP phenotypic expression. By genotyping 25 family members with EPP, they showed that, in trans to a specific FECH mutated allele, only the IVS3-48C polymorphism cosegregated with the low-expression FECH allele in all individuals with overt EPP. Moreover, the IVS3-48C polymorphism cosegregated with the normal-expression allele in all the asymptomatic carriers. Genotyping of 40 additional unrelated individuals with EPP revealed that 38 had an IVS3-48C allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11753383" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Wiman, A., Floderus, Y., Harper, P. <strong>Novel mutations and phenotypic effect of the splice site modulator IVS3-48C in nine Swedish families with erythropoietic protoporphyria.</strong> J. Hum. Genet. 48: 70-76, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12601550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12601550</a>] [<a href="https://doi.org/10.1007/s100380300009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12601550">Wiman et al. (2003)</a> stated that 26 apparently unrelated families with EPP were registered at the Porphyria Centre Sweden. They performed a mutation study and investigation of the splice site modulator IVS3-48C in 9 of the families. Four novel and 2 previously reported FECH mutations were detected. They found that all individuals carrying a mutated allele and IVS3-48C in trans to each other were affected by overt EPP. They thought, however, that mild clinical and biochemical EPP signs may be present in individuals carrying a T at IVS3-48 in trans to a mutated allele, because 1 such case was identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12601550" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Aurizi, C., Schneider-Yin, X., Sorge, F., Macri, A., Minder, E. I., Biolcati, G. <strong>Heterogeneity of mutations in the ferrochelatase gene in Italian patients with erythropoietic protoporphyria.</strong> Molec. Genet. Metab. 90: 402-407, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17196862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17196862</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.10.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17196862">Aurizi et al. (2007)</a> studied 15 Italian families with erythropoietic protoporphyria and identified 10 different FECH mutations, 6 of which were novel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17196862" 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="#19" class="mim-tip-reference" title="Rufenacht, U. B., Gouya, L., Schneider-Yin, X., Puy, H., Schafer, B. W., Aquaron, R., Nordmann, Y., Minder, E. I., Deybach, J. C. <strong>Systematic analysis of molecular defects in the ferrochelatase gene from patients with erythropoietic protoporphyria.</strong> Am. J. Hum. Genet. 62: 1341-1352, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585598</a>] [<a href="https://doi.org/10.1086/301870" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9585598">Rufenacht et al. (1998)</a> found that mutations leading to a null FECH allele were a common feature among 3 EPP pedigrees with liver complications. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9585598" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Bloomer, J., Bruzzone, C., Zhu, L., Scarlett, Y., Magness, S., Brenner, D. <strong>Molecular defects in ferrochelatase in patients with protoporphyria requiring liver transplantation.</strong> J. Clin. Invest. 102: 107-114, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9649563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9649563</a>] [<a href="https://doi.org/10.1172/JCI1347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9649563">Bloomer et al. (1998)</a> focused on the gene mutations responsible for protoporphyria in patients requiring liver transplantation, i.e., those with the most severe phenotype. Mutations of the FECH gene were examined in 8 unrelated patients. RNA was prepared from liver and/or lymphoblasts, and specific reverse transcriptase-nested polymerase chain reactions were amplified and FECH cDNAs sequenced. Products shorter than normal resulted from an exon 3 deletion in 3 patients (<a href="#0008">612386.0008</a> and <a href="#0009">612386.0009</a>), exon 10 deletion in 2 (<a href="#0010">612386.0010</a> and <a href="#0011">612386.0011</a>), exon 2 deletion in 1 (<a href="#0012">612386.0012</a>), and deletion of 5 nucleotides in exon 5 in 1 (<a href="#0013">612386.0013</a>). Sequence of normal-sized products revealed no other mutations. Western blot showed a reduced quantity of normal-sized FECH protein in protoporphyria liver compared to normal liver. Liver FECH activity was reduced more than could be explained by the decrease in FECH protein. The gene mutations found in the most severe phenotype of protoporphyria shared the property of causing a major structural alteration in the FECH protein. <a href="#2" class="mim-tip-reference" title="Bloomer, J., Bruzzone, C., Zhu, L., Scarlett, Y., Magness, S., Brenner, D. <strong>Molecular defects in ferrochelatase in patients with protoporphyria requiring liver transplantation.</strong> J. Clin. Invest. 102: 107-114, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9649563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9649563</a>] [<a href="https://doi.org/10.1172/JCI1347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9649563">Bloomer et al. (1998)</a> suggested that the liver probably contributes to the overproduction of protoporphyrin that results in its own damage, and that the overproduction may increase as liver damage progresses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9649563" 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="Schneider-Yin, X., Gouya, L., Meier-Weinand, A., Deybach, J.-C., Minder, E. I. <strong>New insights into the pathogenesis of erythropoietic protoporphyria and their impact on patient care.</strong> Europ. J. Pediat. 159: 719-725, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11039124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11039124</a>] [<a href="https://doi.org/10.1007/s004310000494" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11039124">Schneider-Yin et al. (2000)</a> reported that a total of 65 different mutations had been identified in the FECH gene in EPP patients. Among the 89 EPP patients who carried a 'null allele' mutation which resulted in the formation of a truncated protein, 18 of them developed EPP-related liver complications. None of the 16 missense mutations identified among 19 patients, on the other hand, were associated with liver disease (p = 0.038). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11039124" 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="#24" class="mim-tip-reference" title="Shah, D. I., Takahashi-Makise, N., Cooney, J. D., Li, L., Schultz, I. J., Pierce, E. L., Narla, A., Seguin, A., Hattangadi, S. M., Medlock, A. E., Langer, N. B., Dailey, T. A., and 18 others. <strong>Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts.</strong> Nature 491: 608-612, 2012. Note: Erratum: Nature 496: 386 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23135403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23135403</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23135403[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/nature11536" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23135403">Shah et al. (2012)</a> described a direct mechanism establishing that Atpif1 (<a href="/entry/614981">614981</a>) regulates the catalytic efficiency of vertebrate Fech to synthesize heme. The loss of Atpif1 impairs hemoglobin synthesis in zebrafish, mouse, and human hematopoietic models as a consequence of diminished Fech activity and elevated mitochondrial pH. To understand the relationship between mitochondrial pH, redox potential, [2Fe-2S] clusters, and Fech activity, <a href="#24" class="mim-tip-reference" title="Shah, D. I., Takahashi-Makise, N., Cooney, J. D., Li, L., Schultz, I. J., Pierce, E. L., Narla, A., Seguin, A., Hattangadi, S. M., Medlock, A. E., Langer, N. B., Dailey, T. A., and 18 others. <strong>Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts.</strong> Nature 491: 608-612, 2012. Note: Erratum: Nature 496: 386 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23135403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23135403</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23135403[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/nature11536" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23135403">Shah et al. (2012)</a> used genetic complementation studies of Fech constructs with or without [2Fe-2S] clusters in 'pinotage' (pnt), a severely anemic zebrafish model, as well as pharmacologic agents modulating mitochondrial pH and redox potential. The presence of [2Fe-2S] cluster renders vertebrate Fech vulnerable to perturbations in Atpif1-regulated mitochondrial pH and redox potential. Therefore, Atpif1 deficiency reduces the efficiency of vertebrate Fech to synthesize heme, resulting in anemia. <a href="#24" class="mim-tip-reference" title="Shah, D. I., Takahashi-Makise, N., Cooney, J. D., Li, L., Schultz, I. J., Pierce, E. L., Narla, A., Seguin, A., Hattangadi, S. M., Medlock, A. E., Langer, N. B., Dailey, T. A., and 18 others. <strong>Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts.</strong> Nature 491: 608-612, 2012. Note: Erratum: Nature 496: 386 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23135403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23135403</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23135403[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/nature11536" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23135403">Shah et al. (2012)</a> concluded that their identification of mitochondrial Atpif1 as a regulator of heme synthesis advanced the understanding of mechanisms regulating mitochondrial heme homeostasis and red blood cell development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23135403" 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>.0001 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs3848519 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3848519;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/rs3848519?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=rs3848519" 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=rs3848519" 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=RCV000000578 OR RCV000455178 OR RCV001517622" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000578, RCV000455178, RCV001517622" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000578...</a>
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<p>In a 27-year-old man with erythropoietic protoporphyria (EPP1; <a href="/entry/177000">177000</a>), born of healthy, nonconsanguineous French parents, <a href="#12" class="mim-tip-reference" title="Lamoril, J., Boulechfar, S., de Verneuil, H., Grandchamp, B., Nordmann, Y., Deybach, J.-C. <strong>Human erythropoietic protoporphyria: two point mutations in the ferrochelatase gene.</strong> Biochem. Biophys. Res. Commun. 181: 594-599, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1755842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1755842</a>] [<a href="https://doi.org/10.1016/0006-291x(91)91231-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1755842">Lamoril et al. (1991)</a> identified compound heterozygosity for 2 mutations in the FECH gene: a 163G-T transversion resulting in a gly55-to-cys (G55C) substitution inherited from his father, and an 801G-A transition resulting in a met267-to-ile (M267I; <a href="#0002">612386.0002</a>) inherited from his mother. Burning and itching of skin on exposure to sunlight with accompanying edema and erythema appeared when the patient was 3 years old. The diagnosis of EPP was made at age 17. He had no anemia and liver tests were normal without signs of cholelithiasis. A 94% decrease in ferrochelatase activity was found in lymphocytes. Both parents had lymphocyte ferrochelatase activities decreased to 50% of normal. Neither had clinical or biochemical signs of EPP. Neither mutation was present in an unrelated patient with EPP, indicating genetic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1755842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs118204037 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204037;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/rs118204037?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=rs118204037" 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=rs118204037" 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=RCV000000579 OR RCV001794424" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000579, RCV001794424" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000579...</a>
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<p>For discussion of the met267-to-ile (M267I) mutation in the FECH gene that was found in compound heterozygous state in a patient with erythropoietic protoporphyria (EPP1; <a href="/entry/177000">177000</a>) by <a href="#12" class="mim-tip-reference" title="Lamoril, J., Boulechfar, S., de Verneuil, H., Grandchamp, B., Nordmann, Y., Deybach, J.-C. <strong>Human erythropoietic protoporphyria: two point mutations in the ferrochelatase gene.</strong> Biochem. Biophys. Res. Commun. 181: 594-599, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1755842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1755842</a>] [<a href="https://doi.org/10.1016/0006-291x(91)91231-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1755842">Lamoril et al. (1991)</a>, see <a href="#0001">612386.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1755842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
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FECH, IVS1AS, C-T, -23
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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> rs2269219 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2269219;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/rs2269219?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=rs2269219" 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=rs2269219" 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=RCV000000580 OR RCV000415389 OR RCV001520174" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000580, RCV000415389, RCV001520174" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000580...</a>
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<p>In EBV-transformed lymphoblastoid cells from a 12-year-old white girl with cutaneous photosensitivity characteristic of erythropoietic protoporphyria (EPP1; <a href="/entry/177000">177000</a>), <a href="#13" class="mim-tip-reference" title="Nakahashi, Y., Fujita, H., Taketani, S., Ishida, N., Kappas, A., Sassa, S. <strong>The molecular defect of ferrochelatase in a patient with erythropoietic protoporphyria.</strong> Proc. Nat. Acad. Sci. 89: 281-285, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1729699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1729699</a>] [<a href="https://doi.org/10.1073/pnas.89.1.281" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1729699">Nakahashi et al. (1992)</a> found that ferrochelatase activity, immunochemically quantifiable protein, and mRNA content were about one-half normal. In contrast, the rate of transcription of FECH mRNA in the proband's cells was normal, suggesting that decreased FECH mRNA was due to unstable transcript. cDNA clones encoding ferrochelatase in the proband, isolated by amplification using the polymerase chain reaction (PCR), were found either to encode the normal protein or an abnormal protein that lacked exon 2. Genomic DNA analysis demonstrated that the abnormal allele had a point mutation, C-to-T, near the acceptor site of intron 1. The findings in this patient were thought to confirm autosomal dominant inheritance, at least for this mutation. Both intron 1 and intron 2 of the FECH gene are exceedingly long (8 kb and 7 kb, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1729699" 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 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
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FECH, PHE417SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs118204039 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204039;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=rs118204039" 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=rs118204039" 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=RCV000000581" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000581" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000581</a>
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<p>In a patient with erythropoietic protoporphyria (EPP1; <a href="/entry/177000">177000</a>), <a href="#6" class="mim-tip-reference" title="Brenner, D. A., Didier, J. M., Frasier, F., Christensen, S. R., Evans, G. A., Dailey, H. A. <strong>A molecular defect in human protoporphyria.</strong> Am. J. Hum. Genet. 50: 1203-1210, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1376018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1376018</a>]" pmid="1376018">Brenner et al. (1992)</a> identified a point mutation resulting in the conversion of codon 417 from phenylalanine (TTC) to serine (TCC) in the carboxy-terminal portion of the FECH protein. Expression of recombinant ferrochelatase in E. coli demonstrated a marked deficiency in activity of the mutant protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1376018" 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 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
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FECH, IVS9DS, G-A, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786205245 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205245;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=rs786205245" 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=rs786205245" 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=RCV000000582" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000582" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000582</a>
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<p><a href="#14" class="mim-tip-reference" title="Nakahashi, Y., Miyazaki, H., Kadota, Y., Naitoh, Y., Inoue, K., Yamamoto, M., Hayashi, N., Taketani, S. <strong>Molecular defect in human erythropoietic protoporphyria with fatal liver failure.</strong> Hum. Genet. 91: 303-306, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8500787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8500787</a>] [<a href="https://doi.org/10.1007/BF00217346" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8500787">Nakahashi et al. (1993)</a> investigated a 37-year-old Japanese man with erythropoietic protoporphyria (EPP1; <a href="/entry/177000">177000</a>) who had experienced photosensitivity from early childhood and developed fatal liver failure characterized by acute onset of jaundice as described by <a href="#4" class="mim-tip-reference" title="Bonkovsky, H. L., Schned, A. R. <strong>Fatal liver failure in protoporphyria: synergism between ethanol excess and the genetic defect.</strong> Gastroenterology 90: 191-201, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3940245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3940245</a>]" pmid="3940245">Bonkovsky and Schned (1986)</a>. They found that the FECH cDNA lacked exon 9 due to a G-to-A transition at the first position of the donor site of intron 9. The identical mutation was detected in affected family members by allele-specific oligonucleotide hybridization analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3940245+8500787" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
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FECH, IVS10DS, A-G, +3
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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> rs202147607 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs202147607;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/rs202147607?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=rs202147607" 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=rs202147607" 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=RCV000000583 OR RCV001851512" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000583, RCV001851512" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000583...</a>
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<p><a href="#20" class="mim-tip-reference" title="Sarkany, R. P. E., Alexander, G. J. M. A., Cox, T. M. <strong>Recessive inheritance of erythropoietic protoporphyria with liver failure.</strong> Lancet 343: 1394-1396, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7910885/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7910885</a>] [<a href="https://doi.org/10.1016/s0140-6736(94)92525-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7910885">Sarkany et al. (1994)</a> reported a family in which a brother and sister developed liver failure in adolescence. The parents were healthy and nonconsanguineous, and there was no family history of photosensitivity or liver disease. Both sibs had had erythropoietic protoporphyria (EPP1; <a href="/entry/177000">177000</a>) with severe photosensitivity since infancy. The brother developed rapidly progressive hepatic failure at age 13. He received a liver transplant (<a href="#18" class="mim-tip-reference" title="Polson, R. J., Lim, C. K., Rolles, K., Calne, R. Y., Williams, R. <strong>The effect of liver transplantation in a 13-year-old boy with erythropoietic protoporphyria.</strong> Transplantation 46: 386-389, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3047929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3047929</a>] [<a href="https://doi.org/10.1097/00007890-198809000-00010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3047929">Polson et al., 1988</a>), but died after a second transplant for chronic graft rejection. At age 17, his younger sister developed hepatic failure and also required transplantation; she remained well 14 months later. Histologic examination confirmed the diagnosis of protoporphyrin hepatopathy in both sibs. Although both parents were asymptomatic, each showed partial deficiency of ferrochelatase and each was shown to be heterozygous for a distinct mutation in the FECH gene. Both were splice site mutations. The mutation in the mother was an A-to-G change at position +3 of the donor site of intron 10; the mutation in the father was a T-to-G transversion at nucleotide 1088 located 6 bases upstream of the acceptor splice site for intron 10 (<a href="#0007">612386.0007</a>). Thus, the affected sibs were compound heterozygotes. As expected from their positions at the donor site and near the acceptor site, the mutations impaired splicing of exon 10 of the ferrochelatase transcript. The paternal mutation additionally substituted a glycine for valine at residue 363 (V363G), which may further reduce enzyme activity. The predominant effect of the mutations, however, was to exclude the 20 amino acids encoded by exon 10, which, except for the valine, have been conserved in vertebrate evolution. <a href="#20" class="mim-tip-reference" title="Sarkany, R. P. E., Alexander, G. J. M. A., Cox, T. M. <strong>Recessive inheritance of erythropoietic protoporphyria with liver failure.</strong> Lancet 343: 1394-1396, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7910885/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7910885</a>] [<a href="https://doi.org/10.1016/s0140-6736(94)92525-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7910885">Sarkany et al. (1994)</a> noted that the heterozygous parents had fluorescent red cells (fluorocytes) and increased red cell protoporphyrin concentrations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3047929+7910885" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs118204040 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204040;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=rs118204040" 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=rs118204040" 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=RCV000000584" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000584" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000584</a>
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<p>For discussion of the val363-to-gly (V363G) mutation in the FECH gene that was found in compound heterozygous state in sibs with erythropoietic protoporphyria (EPP1; <a href="/entry/177000">177000</a>) by <a href="#20" class="mim-tip-reference" title="Sarkany, R. P. E., Alexander, G. J. M. A., Cox, T. M. <strong>Recessive inheritance of erythropoietic protoporphyria with liver failure.</strong> Lancet 343: 1394-1396, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7910885/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7910885</a>] [<a href="https://doi.org/10.1016/s0140-6736(94)92525-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7910885">Sarkany et al. (1994)</a>, see <a href="#0006">612386.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7910885" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs149067146 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs149067146;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/rs149067146?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=rs149067146" 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=rs149067146" 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=RCV000000585 OR RCV001851513" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000585, RCV001851513" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000585...</a>
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<p>In 2 unrelated patients with erythropoietic protoporphyria (EPP1; <a href="/entry/177000">177000</a>) who had undergone liver transplantation, <a href="#2" class="mim-tip-reference" title="Bloomer, J., Bruzzone, C., Zhu, L., Scarlett, Y., Magness, S., Brenner, D. <strong>Molecular defects in ferrochelatase in patients with protoporphyria requiring liver transplantation.</strong> J. Clin. Invest. 102: 107-114, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9649563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9649563</a>] [<a href="https://doi.org/10.1172/JCI1347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9649563">Bloomer et al. (1998)</a> found a splice site mutation in heterozygous state (IVS3+2T-G) in the FECH gene, resulting in deletion of exon 3 (amino acids 66-105). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9649563" 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">rs786205246 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205246;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=rs786205246" 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=rs786205246" 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=RCV000000586" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000586" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000586</a>
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<p>In a patient with erythropoietic protoporphyria (EPP1; <a href="/entry/177000">177000</a>) who had undergone liver transplantation, <a href="#2" class="mim-tip-reference" title="Bloomer, J., Bruzzone, C., Zhu, L., Scarlett, Y., Magness, S., Brenner, D. <strong>Molecular defects in ferrochelatase in patients with protoporphyria requiring liver transplantation.</strong> J. Clin. Invest. 102: 107-114, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9649563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9649563</a>] [<a href="https://doi.org/10.1172/JCI1347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9649563">Bloomer et al. (1998)</a> found a splice site mutation in heterozygous state (IVS3+6A-C) in the FECH gene, resulting in deletion of exon 3 (amino acids 66-105). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9649563" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs879255507 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255507;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/rs879255507?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=rs879255507" 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=rs879255507" 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=RCV000000587 OR RCV003555879" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000587, RCV003555879" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000587...</a>
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<p>By genomic sequence analysis in a patient with protoporphyria (EPP1; <a href="/entry/177000">177000</a>) requiring liver transplantation, <a href="#2" class="mim-tip-reference" title="Bloomer, J., Bruzzone, C., Zhu, L., Scarlett, Y., Magness, S., Brenner, D. <strong>Molecular defects in ferrochelatase in patients with protoporphyria requiring liver transplantation.</strong> J. Clin. Invest. 102: 107-114, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9649563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9649563</a>] [<a href="https://doi.org/10.1172/JCI1347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9649563">Bloomer et al. (1998)</a> detected an A-to-T transversion at position -3 of the donor site of intron 10 (1135A-T) in the FECH gene, resulting in deletion of exon 10 (amino acids 360-379). This mutation had been reported in heterozygous state by <a href="#26" class="mim-tip-reference" title="Wang, X., Poh-Fitzpatrick, M., Carriero, D., Ostasiewicz, L., Chen, T., Taketani, S., Piomelli, S. <strong>A novel mutation in erythropoietic protoporphyria: an aberrant ferrochelatase mRNA caused by exon skipping during RNA splicing.</strong> Biochim. Biophys. Acta 1181: 198-200, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8481408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8481408</a>] [<a href="https://doi.org/10.1016/0925-4439(93)90112-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8481408">Wang et al. (1993)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9649563+8481408" 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>.0011 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs764466739 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs764466739;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/rs764466739?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=rs764466739" 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=rs764466739" 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=RCV000000588 OR RCV003555880 OR RCV004754228" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000588, RCV003555880, RCV004754228" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000588...</a>
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<p><a href="#2" class="mim-tip-reference" title="Bloomer, J., Bruzzone, C., Zhu, L., Scarlett, Y., Magness, S., Brenner, D. <strong>Molecular defects in ferrochelatase in patients with protoporphyria requiring liver transplantation.</strong> J. Clin. Invest. 102: 107-114, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9649563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9649563</a>] [<a href="https://doi.org/10.1172/JCI1347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9649563">Bloomer et al. (1998)</a> found deletion of a single adenine nucleotide at position 1135 or 1136 of the FECH gene in a patient with protoporphyria (EPP1; <a href="/entry/177000">177000</a>) requiring liver transplantation. <a href="#2" class="mim-tip-reference" title="Bloomer, J., Bruzzone, C., Zhu, L., Scarlett, Y., Magness, S., Brenner, D. <strong>Molecular defects in ferrochelatase in patients with protoporphyria requiring liver transplantation.</strong> J. Clin. Invest. 102: 107-114, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9649563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9649563</a>] [<a href="https://doi.org/10.1172/JCI1347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9649563">Bloomer et al. (1998)</a> considered that the exon 10 mutations described by them (see <a href="#0010">612386.0010</a>) indicated that the region around nucleotide 1135 was critical to normal splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9649563" 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>.0012 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786205247 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205247;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=rs786205247" 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=rs786205247" 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=RCV000000589" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000589" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000589</a>
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<p>In a patient with protoporphyria (EPP1; <a href="/entry/177000">177000</a>) who had undergone liver transplantation, <a href="#2" class="mim-tip-reference" title="Bloomer, J., Bruzzone, C., Zhu, L., Scarlett, Y., Magness, S., Brenner, D. <strong>Molecular defects in ferrochelatase in patients with protoporphyria requiring liver transplantation.</strong> J. Clin. Invest. 102: 107-114, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9649563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9649563</a>] [<a href="https://doi.org/10.1172/JCI1347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9649563">Bloomer et al. (1998)</a> identified a splice site mutation (IVS2+11A-G) in heterozygous state in the FECH gene, resulting in deletion of exon 2 and a truncated protein of 29 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9649563" 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>.0013 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
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FECH, 5-BP DEL, NT580
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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> rs786205248 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205248;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/rs786205248?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=rs786205248" 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=rs786205248" 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=RCV000000590 OR RCV003555881" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000590, RCV003555881" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000590...</a>
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<p>In a patient with erythropoietic protoporphyria (EPP1; <a href="/entry/177000">177000</a>) who required liver transplantation, <a href="#2" class="mim-tip-reference" title="Bloomer, J., Bruzzone, C., Zhu, L., Scarlett, Y., Magness, S., Brenner, D. <strong>Molecular defects in ferrochelatase in patients with protoporphyria requiring liver transplantation.</strong> J. Clin. Invest. 102: 107-114, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9649563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9649563</a>] [<a href="https://doi.org/10.1172/JCI1347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9649563">Bloomer et al. (1998)</a> identified deletion of nucleotides 580-584 in exon 5 of the FECH gene, resulting in a frameshift and a truncated protein of 208 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9649563" 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>.0014 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
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FECH, ASN408LYS, PRO409SER, AND CYS411GLY
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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> rs146899669 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs146899669;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/rs146899669?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=rs146899669" 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=rs146899669" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606803 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606803;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=rs267606803" 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=rs267606803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606804 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606804;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=rs267606804" 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=rs267606804" 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=RCV000000591 OR RCV001857788" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000591, RCV001857788" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000591...</a>
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<p>In a patient with erythropoietic protoporphyria (EPP1; <a href="/entry/177000">177000</a>), <a href="#21" class="mim-tip-reference" title="Schneider-Yin, X., Gouya, L., Dorsey, M., Rufenacht, U., Deybach, J.-C., Ferreira, G. C. <strong>Mutations in the iron-sulfur cluster ligands of the human ferrochelatase lead to erythropoietic protoporphyria.</strong> Blood 96: 1545-1549, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10942404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10942404</a>]" pmid="10942404">Schneider-Yin et al. (2000)</a> found heterozygosity for a triple mutation in the FECH gene: 1224T-A, 1225C-T, and 1231T-G, leading to asn408-to-lys/pro409-to-ser/cys411-to-gly amino acid changes. All 3 mutations were absent from the FECH gene of the patient's mother, suggesting that all 3 were aligned on the FECH allele derived from the father. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10942404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0015 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
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FECH, IVS3AS, T-C, -48
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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> rs2272783 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2272783;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/rs2272783?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=rs2272783" 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=rs2272783" 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=RCV000000592 OR RCV000414979 OR RCV001195427 OR RCV001381522" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000592, RCV000414979, RCV001195427, RCV001381522" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000592...</a>
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<p>Erythropoietic protoporphyria-1 (EPP1; <a href="/entry/177000">177000</a>) most often results from inheritance of this low-expression mutation (IVS3-48C) in trans with a null FECH allele (<a href="#10" class="mim-tip-reference" title="Herrero, C., To-Figueras, J., Badenas, C., Mendez, M., Serrano, P., Enriquez-Salamanca, R., Lecha, M. <strong>Clinical, biochemical, and genetic study of 11 patients with erythropoietic protoporphyria including one with homozygous disease.</strong> Arch. Derm. 143: 1125-1129, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17875872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17875872</a>] [<a href="https://doi.org/10.1001/archderm.143.9.1125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17875872">Herrero et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17875872" 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="Gouya, L., Puy, H., Robreau, A.-M., Bourgeois, M., Lamoril, J., Da Silva, V., Grandchamp, B., Deybach, J.-C. <strong>The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH.</strong> Nature Genet. 30: 27-28, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11753383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11753383</a>] [<a href="https://doi.org/10.1038/ng809" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11753383">Gouya et al. (2002)</a> described an intronic single-nucleotide polymorphism, IVS3-48T-C, that modulates the use of a constitutive aberrant acceptor splice site. The aberrantly spliced mRNA is degraded by a nonsense-mediated decay mechanism, producing a decreased steady-state level of mRNA and the additional FECH enzyme deficiency necessary for EPP phenotypic expression. <a href="#8" class="mim-tip-reference" title="Gouya, L., Puy, H., Robreau, A.-M., Bourgeois, M., Lamoril, J., Da Silva, V., Grandchamp, B., Deybach, J.-C. <strong>The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH.</strong> Nature Genet. 30: 27-28, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11753383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11753383</a>] [<a href="https://doi.org/10.1038/ng809" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11753383">Gouya et al. (2002)</a> suggested that this explained the incomplete penetrance of EPP. Using 25 families with EPP caused by identified mutations, they unambiguously determined the haplotypes of 19 independent chromosomes bearing a normal-expression allele and 23 independent chromosomes bearing a low-expression allele in trans to the mutated allele in asymptomatic carrier parents and individuals with overt EPP, respectively. By genotyping of 25 family members with EPP, they showed that, in trans to a specific FECH mutated allele, only the IVS3-48C polymorphism cosegregated with low-expression FECH allele in all individuals with overt EPP. Moreover, the IVS3-48T polymorphism cosegregated with the normal-expression allele in all the asymptomatic carriers. Genotyping of 40 additional unrelated individuals with EPP revealed that 38 had an IVS3-48C allele. Analysis of the intron 3/exon 4 sequence revealed the presence of a cryptic acceptor splice site 63 bp upstream from the one that is normally used. To test the effect of the IVS3-48T-C transition on splicing efficiency, <a href="#8" class="mim-tip-reference" title="Gouya, L., Puy, H., Robreau, A.-M., Bourgeois, M., Lamoril, J., Da Silva, V., Grandchamp, B., Deybach, J.-C. <strong>The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH.</strong> Nature Genet. 30: 27-28, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11753383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11753383</a>] [<a href="https://doi.org/10.1038/ng809" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11753383">Gouya et al. (2002)</a> subcloned in a eukaryotic expression vector a 1,936-bp genomic fragment spanning exons 3-4 that differed only at the T/C nucleotide. Transfection of the IVS3-48C and IVS3-48T minigenes showed that in both cases the physiologic and the predicted cryptic acceptor sites were used, but with different efficiency. The IVS3-48C minigene gave rise to 40% aberrantly spliced mRNA, and the IVS3-48T minigene to only 20%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11753383" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To confirm in a larger cohort that the low expression of a wildtype allelic variant is generally required for EPP to be clinically expressed, <a href="#9" class="mim-tip-reference" title="Gouya, L., Puy, H., Robreau, A.-M., Lyoumi, S., Lamoril, J., Da Silva, V., Grandchamp, B., Deybach, J.-C. <strong>Modulation of penetrance by the wild-type allele in dominantly inherited erythropoietic protoporphyria and acute hepatic porphyrias.</strong> Hum. Genet. 114: 256-262, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14669009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14669009</a>] [<a href="https://doi.org/10.1007/s00439-003-1059-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14669009">Gouya et al. (2004)</a> studied 55 patients and a control group of 80 unrelated subjects of Caucasian origin. They confirmed that the wildtype low-expressed allele phenomenon is usually operative in a mechanism suggesting incomplete penetrance in EPP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14669009" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Gouya, L., Martin-Schmitt, C., Robreau, A.-M., Austerlitz, F., Da Silva, V., Brun, P., Simonin, S., Lyoumi, S., Grandchamp, B., Beaumont, C., Puy, H., Deybach, J.-C. <strong>Contribution of a common single-nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria.</strong> Am. J. Hum. Genet. 78: 2-14, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16385445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16385445</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16385445[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/10.1086/498620" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16385445">Gouya et al. (2006)</a> showed that the frequency of the IVS3-48C allele differed from 43% in Japanese to less than 1% in black West Africans. They concluded that the mutation may have occurred not long after the Diaspora out of Africa. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16385445" 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>.0016 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514476 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514476;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=rs397514476" 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=rs397514476" 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=RCV000023941" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023941" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023941</a>
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<p>In a 15-year-old girl with erythropoietic protoporphyria (EPP1; <a href="/entry/177000">177000</a>), <a href="#10" class="mim-tip-reference" title="Herrero, C., To-Figueras, J., Badenas, C., Mendez, M., Serrano, P., Enriquez-Salamanca, R., Lecha, M. <strong>Clinical, biochemical, and genetic study of 11 patients with erythropoietic protoporphyria including one with homozygous disease.</strong> Arch. Derm. 143: 1125-1129, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17875872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17875872</a>] [<a href="https://doi.org/10.1001/archderm.143.9.1125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17875872">Herrero et al. (2007)</a> identified a homozygous 553G-A transition in exon 5 of the FECH gene, resulting in an ala185-to-thr (A185T) substitution. She was homozygous for the T variant of the IVS3-48T-C polymorphism (see <a href="#0015">612386.0015</a>). The residual activity of the A185T mutation was 4% of normal. Her parents, who were not known to be related, and her sister, all asymptomatic, were heterozygous for the A185T mutation and none harbored the low expression IVS3-48C allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17875872" 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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Aurizi, C., Schneider-Yin, X., Sorge, F., Macri, A., Minder, E. I., Biolcati, G.
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<strong>Heterogeneity of mutations in the ferrochelatase gene in Italian patients with erythropoietic protoporphyria.</strong>
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[<a href="https://doi.org/10.1016/j.ymgme.2006.10.012" target="_blank">Full Text</a>]
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Bloomer, J., Bruzzone, C., Zhu, L., Scarlett, Y., Magness, S., Brenner, D.
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<strong>Molecular defects in ferrochelatase in patients with protoporphyria requiring liver transplantation.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9649563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9649563</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9649563" 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/JCI1347" target="_blank">Full Text</a>]
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Bloomer, J. R.
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<strong>Characterization of deficient heme synthase activity in protoporphyria with cultured skin fibroblasts.</strong>
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J. Clin. Invest. 65: 321-328, 1980.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7356682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7356682</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7356682" 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/JCI109675" target="_blank">Full Text</a>]
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Bonkovsky, H. L., Schned, A. R.
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<strong>Fatal liver failure in protoporphyria: synergism between ethanol excess and the genetic defect.</strong>
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Gastroenterology 90: 191-201, 1986.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3940245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3940245</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3940245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bonkowsky, H. L., Bloomer, J. R., Ebert, P. S., Mahoney, M. J.
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<strong>Heme synthetase deficiency in human protoporphyria: demonstration of the defect in liver and cultured skin fibroblasts.</strong>
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J. Clin. Invest. 56: 1139-1148, 1975.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1184741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1184741</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1184741" 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/JCI108189" target="_blank">Full Text</a>]
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Brenner, D. A., Didier, J. M., Frasier, F., Christensen, S. R., Evans, G. A., Dailey, H. A.
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<strong>A molecular defect in human protoporphyria.</strong>
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Am. J. Hum. Genet. 50: 1203-1210, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1376018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1376018</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1376018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Gouya, L., Martin-Schmitt, C., Robreau, A.-M., Austerlitz, F., Da Silva, V., Brun, P., Simonin, S., Lyoumi, S., Grandchamp, B., Beaumont, C., Puy, H., Deybach, J.-C.
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<strong>Contribution of a common single-nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria.</strong>
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Am. J. Hum. Genet. 78: 2-14, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16385445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16385445</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16385445[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=16385445" 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/10.1086/498620" target="_blank">Full Text</a>]
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Gouya, L., Puy, H., Robreau, A.-M., Bourgeois, M., Lamoril, J., Da Silva, V., Grandchamp, B., Deybach, J.-C.
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<strong>The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH.</strong>
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Nature Genet. 30: 27-28, 2002.
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[<a href="https://doi.org/10.1111/j.1432-1033.1992.tb16771.x" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Wang1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, X., Poh-Fitzpatrick, M., Carriero, D., Ostasiewicz, L., Chen, T., Taketani, S., Piomelli, S.
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<strong>A novel mutation in erythropoietic protoporphyria: an aberrant ferrochelatase mRNA caused by exon skipping during RNA splicing.</strong>
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Biochim. Biophys. Acta 1181: 198-200, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8481408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8481408</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8481408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0925-4439(93)90112-e" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Whitcombe1991" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Whitcombe, D. M., Carter, N. P., Albertson, D. G., Smith, S. J., Rhodes, D. A., Cox, T. M.
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<strong>Assignment of the human ferrochelatase gene (FECH) and a locus for protoporphyria to chromosome 18q22.</strong>
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Genomics 11: 1152-1154, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1783383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1783383</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1783383" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0888-7543(91)90044-f" target="_blank">Full Text</a>]
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</p>
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<a id="28" class="mim-anchor"></a>
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<a id="Wiman2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wiman, A., Floderus, Y., Harper, P.
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<strong>Novel mutations and phenotypic effect of the splice site modulator IVS3-48C in nine Swedish families with erythropoietic protoporphyria.</strong>
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J. Hum. Genet. 48: 70-76, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12601550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12601550</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12601550" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s100380300009" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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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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Hilary J. Vernon - updated : 05/29/2020
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 12/14/2012<br>Ada Hamosh - updated : 12/13/2012<br>Carol A. Bocchini - updated : 8/26/2011
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Carol A. Bocchini : 11/3/2008
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</span>
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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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carol : 05/29/2020
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/19/2018<br>joanna : 07/01/2016<br>carol : 5/18/2015<br>mcolton : 5/8/2015<br>carol : 9/29/2014<br>alopez : 4/24/2013<br>alopez : 12/21/2012<br>terry : 12/14/2012<br>terry : 12/13/2012<br>terry : 9/1/2011<br>carol : 8/26/2011<br>carol : 8/26/2011<br>carol : 6/1/2011<br>carol : 11/7/2008<br>carol : 11/6/2008
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</span>
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<div class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 612386
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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FERROCHELATASE; FECH
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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HEME SYNTHASE<br />
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HEME SYNTHETASE<br />
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IRON CHELATASE
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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: FECH</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: 18q21.31
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Genomic coordinates <span class="small">(GRCh38)</span> : 18:57,544,377-57,586,702 </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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<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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<td rowspan="1">
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<span class="mim-font">
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18q21.31
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</td>
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<td>
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<span class="mim-font">
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Protoporphyria, erythropoietic, 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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177000
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tbody>
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</table>
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<div>
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<br />
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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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<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>Ferrochelatase (FECH; EC 4.99.1.1), the terminal enzyme of the heme biosynthetic pathway, catalyzes the insertion of iron into protoporphyrin to form heme.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By screening a human placenta cDNA library with a radiolabeled fragment of mouse Fech cDNA, Nakahashi et al. (1990) cloned a cDNA for human ferrochelatase. The deduced protein contains 423 amino acids and has a molecular mass of about 48 kD. Sequence analysis showed that the mature protein has 369 amino acids with a putative leader sequence of 54 amino acids and a molecular mass of about 42 kD. The human and mouse enzymes share 88% sequence identity. Northern blot analysis detected 2 mRNAs of 2.5 and 1.6 kb in K562 and HepG2 cells. </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Evolution</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>Gouya et al. (2006) estimated the neutrality of sequence differences found between human and chimpanzee FECH genes, by calculating the ratio of nonsynonymous to synonymous mutations. Restricting their calculations to the coding region for the mature part of the protein, they found strong evidence of negative Darwinian selection of the mutant altering the function of the protein. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Whitcombe et al. (1991) mapped the FECH gene to chromosome 18 by hybridization of cDNA to sorted chromosomes. Subchromosomal localization to 18q22 was achieved by in situ hybridization. By means of fluorescence in situ hybridization (FISH), Inazawa et al. (1991) demonstrated that the FECH gene is located on band 18q21.3. Brenner et al. (1992) mapped the FECH gene to 18q21.3 by chromosomal in situ suppression hybridization. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
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<p>Taketani et al. (1992) demonstrated that the FECH gene contains 11 exons and has a minimum size of about 45 kb. </p>
|
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</span>
|
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<div>
|
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene Function</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
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<p>In patients with erythropoietic porphyria (EPP; 177000), Bonkowsky et al. (1975) and Bloomer (1980) demonstrated reduction in activity of ferrochelatase to 10 to 25% of normal levels. </p><p>Sellers et al. (1998) engineered recombinant human ferrochelatase to have individual exon deletions corresponding to exons 3 through 11. When expressed in E. coli, none of these possessed significant enzyme activity and all lacked the 2Fe-2S cluster. One of the human missense mutations, F417S (612386.0004), and a series of amino acid replacements at this site (i.e., F417W, F417Y, and F417L) were found, with the exception of F417L, to lack enzyme activity and did not contain the 2Fe-2S cluster in vivo or as isolated in vitro. </p><p>Ohgari et al. (2005) coexpressed human ferrochelatase carrying His- and HA-tags in a tandem fashion in E. coli and found that ferrochelatase formed a homodimer. Homodimers of missense-mutated enzyme were produced in small amounts and showed very low activity. Heterodimers with wildtype and missense-mutated enzyme had reduced, but significant, enzymatic activity without a marked change of Km values for substrates. Heat treatment led to a rapid inactivation of the heterodimeric mutants, indicating instability. Ohgari et al. (2005) hypothesized that instability of the heterodimer containing normal and mutated ferrochelatase, as well as the low production levels due to the structural defect of the mutant protein, causes the weak enzymatic activity of ferrochelatase in EPP patients. </p><p>Phillips et al. (2019) studied EBV-transformed lymphoblastoid cells from 10 individuals with X-linked erythropoietic protoporphyria (XLEPP; 300752) and ALAS2 (301300) mutations, 20 individuals with erythropoietic protoporphyria-1 (EPP1; 177000) with compound heterozygous FECH mutations (10 patients with the low-expression IVS3-48C-T splicing mutation (612386.0015) and a cys422-to-gly substitution and 10 with the IVS3-48C-T splicing mutation and a nonsense or splicing null mutation), and 21 controls. Phillips et al. (2019) found that cells from all of the patients had reduced FECH enzyme activity compared with controls and that the decrease in FECH enzyme activity strongly correlated to MFRN1 (SLC25A37; 610387) mRNA levels. Phillips et al. (2019) also found a reduction in mitochondrial iron levels in patients with EPP1 with FECH IVS3-48C-T/nonsense mutations. </p>
|
|
</span>
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<div>
|
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Molecular Genetics</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In a patient with erythropoietic protoporphyria (EPP1; 177000), Lamoril et al. (1991) found compound heterozygosity for 2 mutations in the FECH gene (612386.0001-612386.0002). Each parent was heterozygous for one of the mutations. </p><p>Rufenacht et al. (1998) conducted a systematic mutation analysis of the FECH gene, following a procedure that combines the exon-by-exon denaturing gradient gel electrophoresis screening of FECH genomic DNA and direct sequencing. They characterized 20 different mutations, 15 of which were described for the first time, in 26 of 29 EPP patients of Swiss and French origin. All the EPP patients, including those with liver complications, were heterozygous for the mutations identified in the FECH gene. The deleterious effect of all missense mutations was assessed by bacterial expression of the respective FECH cDNAs generated by site-directed mutagenesis. </p><p>Schneider-Yin et al. (2000) identified 5 new mutations in patients with EPP. One was a triple point mutation (612386.0014). </p><p>Schneider-Yin et al. (2000) pointed out that the genetic constitution of a patient with overt EPP consists of a mutated FECH allele and a 'low expressed' normal allele; that of an asymptomatic carrier is a combination of a mutated and a normally expressed FECH allele. They stated that the identification of the 'low expressed' allele was facilitated by haplotype analysis using 2 single-nucleotide polymorphisms (SNPs): -251A-G in the promoter region and IVS1-23C-T. </p><p>Using haplotype segregation analysis, Gouya et al. (2002) showed that the mechanism for the low expression of FECH is an IVS3-48T-C polymorphism (612386.0015) that modulates the use of a constitutive aberrant acceptor splice site. The aberrantly spliced mRNA is degraded by a nonsense-mediated decay mechanism, producing a decreased steady-state level of mRNA and the additional FECH enzyme deficiency necessary for EPP phenotypic expression. By genotyping 25 family members with EPP, they showed that, in trans to a specific FECH mutated allele, only the IVS3-48C polymorphism cosegregated with the low-expression FECH allele in all individuals with overt EPP. Moreover, the IVS3-48C polymorphism cosegregated with the normal-expression allele in all the asymptomatic carriers. Genotyping of 40 additional unrelated individuals with EPP revealed that 38 had an IVS3-48C allele. </p><p>Wiman et al. (2003) stated that 26 apparently unrelated families with EPP were registered at the Porphyria Centre Sweden. They performed a mutation study and investigation of the splice site modulator IVS3-48C in 9 of the families. Four novel and 2 previously reported FECH mutations were detected. They found that all individuals carrying a mutated allele and IVS3-48C in trans to each other were affected by overt EPP. They thought, however, that mild clinical and biochemical EPP signs may be present in individuals carrying a T at IVS3-48 in trans to a mutated allele, because 1 such case was identified. </p><p>Aurizi et al. (2007) studied 15 Italian families with erythropoietic protoporphyria and identified 10 different FECH mutations, 6 of which were novel. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</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>Rufenacht et al. (1998) found that mutations leading to a null FECH allele were a common feature among 3 EPP pedigrees with liver complications. </p><p>Bloomer et al. (1998) focused on the gene mutations responsible for protoporphyria in patients requiring liver transplantation, i.e., those with the most severe phenotype. Mutations of the FECH gene were examined in 8 unrelated patients. RNA was prepared from liver and/or lymphoblasts, and specific reverse transcriptase-nested polymerase chain reactions were amplified and FECH cDNAs sequenced. Products shorter than normal resulted from an exon 3 deletion in 3 patients (612386.0008 and 612386.0009), exon 10 deletion in 2 (612386.0010 and 612386.0011), exon 2 deletion in 1 (612386.0012), and deletion of 5 nucleotides in exon 5 in 1 (612386.0013). Sequence of normal-sized products revealed no other mutations. Western blot showed a reduced quantity of normal-sized FECH protein in protoporphyria liver compared to normal liver. Liver FECH activity was reduced more than could be explained by the decrease in FECH protein. The gene mutations found in the most severe phenotype of protoporphyria shared the property of causing a major structural alteration in the FECH protein. Bloomer et al. (1998) suggested that the liver probably contributes to the overproduction of protoporphyrin that results in its own damage, and that the overproduction may increase as liver damage progresses. </p><p>Schneider-Yin et al. (2000) reported that a total of 65 different mutations had been identified in the FECH gene in EPP patients. Among the 89 EPP patients who carried a 'null allele' mutation which resulted in the formation of a truncated protein, 18 of them developed EPP-related liver complications. None of the 16 missense mutations identified among 19 patients, on the other hand, were associated with liver disease (p = 0.038). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Shah et al. (2012) described a direct mechanism establishing that Atpif1 (614981) regulates the catalytic efficiency of vertebrate Fech to synthesize heme. The loss of Atpif1 impairs hemoglobin synthesis in zebrafish, mouse, and human hematopoietic models as a consequence of diminished Fech activity and elevated mitochondrial pH. To understand the relationship between mitochondrial pH, redox potential, [2Fe-2S] clusters, and Fech activity, Shah et al. (2012) used genetic complementation studies of Fech constructs with or without [2Fe-2S] clusters in 'pinotage' (pnt), a severely anemic zebrafish model, as well as pharmacologic agents modulating mitochondrial pH and redox potential. The presence of [2Fe-2S] cluster renders vertebrate Fech vulnerable to perturbations in Atpif1-regulated mitochondrial pH and redox potential. Therefore, Atpif1 deficiency reduces the efficiency of vertebrate Fech to synthesize heme, resulting in anemia. Shah et al. (2012) concluded that their identification of mitochondrial Atpif1 as a regulator of heme synthesis advanced the understanding of mechanisms regulating mitochondrial heme homeostasis and red blood cell development. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>16 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</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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FECH, GLY55CYS
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<br />
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SNP: rs3848519,
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gnomAD: rs3848519,
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ClinVar: RCV000000578, RCV000455178, RCV001517622
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 27-year-old man with erythropoietic protoporphyria (EPP1; 177000), born of healthy, nonconsanguineous French parents, Lamoril et al. (1991) identified compound heterozygosity for 2 mutations in the FECH gene: a 163G-T transversion resulting in a gly55-to-cys (G55C) substitution inherited from his father, and an 801G-A transition resulting in a met267-to-ile (M267I; 612386.0002) inherited from his mother. Burning and itching of skin on exposure to sunlight with accompanying edema and erythema appeared when the patient was 3 years old. The diagnosis of EPP was made at age 17. He had no anemia and liver tests were normal without signs of cholelithiasis. A 94% decrease in ferrochelatase activity was found in lymphocytes. Both parents had lymphocyte ferrochelatase activities decreased to 50% of normal. Neither had clinical or biochemical signs of EPP. Neither mutation was present in an unrelated patient with EPP, indicating genetic heterogeneity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</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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FECH, MET267ILE
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<br />
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SNP: rs118204037,
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gnomAD: rs118204037,
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ClinVar: RCV000000579, RCV001794424
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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>For discussion of the met267-to-ile (M267I) mutation in the FECH gene that was found in compound heterozygous state in a patient with erythropoietic protoporphyria (EPP1; 177000) by Lamoril et al. (1991), see 612386.0001. </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 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</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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FECH, IVS1AS, C-T, -23
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<br />
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SNP: rs2269219,
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gnomAD: rs2269219,
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ClinVar: RCV000000580, RCV000415389, RCV001520174
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In EBV-transformed lymphoblastoid cells from a 12-year-old white girl with cutaneous photosensitivity characteristic of erythropoietic protoporphyria (EPP1; 177000), Nakahashi et al. (1992) found that ferrochelatase activity, immunochemically quantifiable protein, and mRNA content were about one-half normal. In contrast, the rate of transcription of FECH mRNA in the proband's cells was normal, suggesting that decreased FECH mRNA was due to unstable transcript. cDNA clones encoding ferrochelatase in the proband, isolated by amplification using the polymerase chain reaction (PCR), were found either to encode the normal protein or an abnormal protein that lacked exon 2. Genomic DNA analysis demonstrated that the abnormal allele had a point mutation, C-to-T, near the acceptor site of intron 1. The findings in this patient were thought to confirm autosomal dominant inheritance, at least for this mutation. Both intron 1 and intron 2 of the FECH gene are exceedingly long (8 kb and 7 kb, respectively). </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 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</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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FECH, PHE417SER
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<br />
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SNP: rs118204039,
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ClinVar: RCV000000581
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a patient with erythropoietic protoporphyria (EPP1; 177000), Brenner et al. (1992) identified a point mutation resulting in the conversion of codon 417 from phenylalanine (TTC) to serine (TCC) in the carboxy-terminal portion of the FECH protein. Expression of recombinant ferrochelatase in E. coli demonstrated a marked deficiency in activity of the mutant protein. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0005 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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|
FECH, IVS9DS, G-A, +1
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<br />
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SNP: rs786205245,
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ClinVar: RCV000000582
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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>Nakahashi et al. (1993) investigated a 37-year-old Japanese man with erythropoietic protoporphyria (EPP1; 177000) who had experienced photosensitivity from early childhood and developed fatal liver failure characterized by acute onset of jaundice as described by Bonkovsky and Schned (1986). They found that the FECH cDNA lacked exon 9 due to a G-to-A transition at the first position of the donor site of intron 9. The identical mutation was detected in affected family members by allele-specific oligonucleotide hybridization analysis. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
|
FECH, IVS10DS, A-G, +3
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<br />
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|
|
SNP: rs202147607,
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|
gnomAD: rs202147607,
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|
|
|
|
ClinVar: RCV000000583, RCV001851512
|
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|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Sarkany et al. (1994) reported a family in which a brother and sister developed liver failure in adolescence. The parents were healthy and nonconsanguineous, and there was no family history of photosensitivity or liver disease. Both sibs had had erythropoietic protoporphyria (EPP1; 177000) with severe photosensitivity since infancy. The brother developed rapidly progressive hepatic failure at age 13. He received a liver transplant (Polson et al., 1988), but died after a second transplant for chronic graft rejection. At age 17, his younger sister developed hepatic failure and also required transplantation; she remained well 14 months later. Histologic examination confirmed the diagnosis of protoporphyrin hepatopathy in both sibs. Although both parents were asymptomatic, each showed partial deficiency of ferrochelatase and each was shown to be heterozygous for a distinct mutation in the FECH gene. Both were splice site mutations. The mutation in the mother was an A-to-G change at position +3 of the donor site of intron 10; the mutation in the father was a T-to-G transversion at nucleotide 1088 located 6 bases upstream of the acceptor splice site for intron 10 (612386.0007). Thus, the affected sibs were compound heterozygotes. As expected from their positions at the donor site and near the acceptor site, the mutations impaired splicing of exon 10 of the ferrochelatase transcript. The paternal mutation additionally substituted a glycine for valine at residue 363 (V363G), which may further reduce enzyme activity. The predominant effect of the mutations, however, was to exclude the 20 amino acids encoded by exon 10, which, except for the valine, have been conserved in vertebrate evolution. Sarkany et al. (1994) noted that the heterozygous parents had fluorescent red cells (fluorocytes) and increased red cell protoporphyrin concentrations. </p>
|
|
</span>
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|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
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|
|
FECH, VAL363GLY
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<br />
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|
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SNP: rs118204040,
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|
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ClinVar: RCV000000584
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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>For discussion of the val363-to-gly (V363G) mutation in the FECH gene that was found in compound heterozygous state in sibs with erythropoietic protoporphyria (EPP1; 177000) by Sarkany et al. (1994), see 612386.0006. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
FECH, IVS3DS, T-G, +2
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|
|
|
<br />
|
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|
|
SNP: rs149067146,
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|
|
|
gnomAD: rs149067146,
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|
|
|
|
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ClinVar: RCV000000585, RCV001851513
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|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated patients with erythropoietic protoporphyria (EPP1; 177000) who had undergone liver transplantation, Bloomer et al. (1998) found a splice site mutation in heterozygous state (IVS3+2T-G) in the FECH gene, resulting in deletion of exon 3 (amino acids 66-105). </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</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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FECH, IVS3DS, A-C, +6
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<br />
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SNP: rs786205246,
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ClinVar: RCV000000586
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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 patient with erythropoietic protoporphyria (EPP1; 177000) who had undergone liver transplantation, Bloomer et al. (1998) found a splice site mutation in heterozygous state (IVS3+6A-C) in the FECH gene, resulting in deletion of exon 3 (amino acids 66-105). </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>.0010 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</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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FECH, EX10DEL
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<br />
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SNP: rs879255507,
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gnomAD: rs879255507,
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ClinVar: RCV000000587, RCV003555879
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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>By genomic sequence analysis in a patient with protoporphyria (EPP1; 177000) requiring liver transplantation, Bloomer et al. (1998) detected an A-to-T transversion at position -3 of the donor site of intron 10 (1135A-T) in the FECH gene, resulting in deletion of exon 10 (amino acids 360-379). This mutation had been reported in heterozygous state by Wang et al. (1993). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0011 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</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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FECH, 1-BP DEL, 1135A
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<br />
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SNP: rs764466739,
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gnomAD: rs764466739,
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ClinVar: RCV000000588, RCV003555880, RCV004754228
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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>Bloomer et al. (1998) found deletion of a single adenine nucleotide at position 1135 or 1136 of the FECH gene in a patient with protoporphyria (EPP1; 177000) requiring liver transplantation. Bloomer et al. (1998) considered that the exon 10 mutations described by them (see 612386.0010) indicated that the region around nucleotide 1135 was critical to normal splicing. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0012 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</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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FECH, IVS2DS, A-G, +11
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<br />
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SNP: rs786205247,
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ClinVar: RCV000000589
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with protoporphyria (EPP1; 177000) who had undergone liver transplantation, Bloomer et al. (1998) identified a splice site mutation (IVS2+11A-G) in heterozygous state in the FECH gene, resulting in deletion of exon 2 and a truncated protein of 29 amino acids. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0013 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</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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FECH, 5-BP DEL, NT580
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<br />
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SNP: rs786205248,
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gnomAD: rs786205248,
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ClinVar: RCV000000590, RCV003555881
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with erythropoietic protoporphyria (EPP1; 177000) who required liver transplantation, Bloomer et al. (1998) identified deletion of nucleotides 580-584 in exon 5 of the FECH gene, resulting in a frameshift and a truncated protein of 208 amino acids. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0014 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</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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FECH, ASN408LYS, PRO409SER, AND CYS411GLY
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<br />
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SNP: rs146899669, rs267606803, rs267606804,
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gnomAD: rs146899669,
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ClinVar: RCV000000591, RCV001857788
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with erythropoietic protoporphyria (EPP1; 177000), Schneider-Yin et al. (2000) found heterozygosity for a triple mutation in the FECH gene: 1224T-A, 1225C-T, and 1231T-G, leading to asn408-to-lys/pro409-to-ser/cys411-to-gly amino acid changes. All 3 mutations were absent from the FECH gene of the patient's mother, suggesting that all 3 were aligned on the FECH allele derived from the father. </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>.0015 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</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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FECH, IVS3AS, T-C, -48
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<br />
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SNP: rs2272783,
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gnomAD: rs2272783,
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ClinVar: RCV000000592, RCV000414979, RCV001195427, RCV001381522
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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>Erythropoietic protoporphyria-1 (EPP1; 177000) most often results from inheritance of this low-expression mutation (IVS3-48C) in trans with a null FECH allele (Herrero et al., 2007). </p><p>Gouya et al. (2002) described an intronic single-nucleotide polymorphism, IVS3-48T-C, that modulates the use of a constitutive aberrant acceptor splice site. The aberrantly spliced mRNA is degraded by a nonsense-mediated decay mechanism, producing a decreased steady-state level of mRNA and the additional FECH enzyme deficiency necessary for EPP phenotypic expression. Gouya et al. (2002) suggested that this explained the incomplete penetrance of EPP. Using 25 families with EPP caused by identified mutations, they unambiguously determined the haplotypes of 19 independent chromosomes bearing a normal-expression allele and 23 independent chromosomes bearing a low-expression allele in trans to the mutated allele in asymptomatic carrier parents and individuals with overt EPP, respectively. By genotyping of 25 family members with EPP, they showed that, in trans to a specific FECH mutated allele, only the IVS3-48C polymorphism cosegregated with low-expression FECH allele in all individuals with overt EPP. Moreover, the IVS3-48T polymorphism cosegregated with the normal-expression allele in all the asymptomatic carriers. Genotyping of 40 additional unrelated individuals with EPP revealed that 38 had an IVS3-48C allele. Analysis of the intron 3/exon 4 sequence revealed the presence of a cryptic acceptor splice site 63 bp upstream from the one that is normally used. To test the effect of the IVS3-48T-C transition on splicing efficiency, Gouya et al. (2002) subcloned in a eukaryotic expression vector a 1,936-bp genomic fragment spanning exons 3-4 that differed only at the T/C nucleotide. Transfection of the IVS3-48C and IVS3-48T minigenes showed that in both cases the physiologic and the predicted cryptic acceptor sites were used, but with different efficiency. The IVS3-48C minigene gave rise to 40% aberrantly spliced mRNA, and the IVS3-48T minigene to only 20%. </p><p>To confirm in a larger cohort that the low expression of a wildtype allelic variant is generally required for EPP to be clinically expressed, Gouya et al. (2004) studied 55 patients and a control group of 80 unrelated subjects of Caucasian origin. They confirmed that the wildtype low-expressed allele phenomenon is usually operative in a mechanism suggesting incomplete penetrance in EPP. </p><p>Gouya et al. (2006) showed that the frequency of the IVS3-48C allele differed from 43% in Japanese to less than 1% in black West Africans. They concluded that the mutation may have occurred not long after the Diaspora out of Africa. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 PROTOPORPHYRIA, ERYTHROPOIETIC, 1</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
FECH, ALA185THR
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<br />
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SNP: rs397514476,
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|
|
|
|
ClinVar: RCV000023941
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 15-year-old girl with erythropoietic protoporphyria (EPP1; 177000), Herrero et al. (2007) identified a homozygous 553G-A transition in exon 5 of the FECH gene, resulting in an ala185-to-thr (A185T) substitution. She was homozygous for the T variant of the IVS3-48T-C polymorphism (see 612386.0015). The residual activity of the A185T mutation was 4% of normal. Her parents, who were not known to be related, and her sister, all asymptomatic, were heterozygous for the A185T mutation and none harbored the low expression IVS3-48C allele. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<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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Aurizi, C., Schneider-Yin, X., Sorge, F., Macri, A., Minder, E. I., Biolcati, G.
|
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<strong>Heterogeneity of mutations in the ferrochelatase gene in Italian patients with erythropoietic protoporphyria.</strong>
|
|
Molec. Genet. Metab. 90: 402-407, 2007.
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[PubMed: 17196862]
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[Full Text: https://doi.org/10.1016/j.ymgme.2006.10.012]
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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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Bloomer, J., Bruzzone, C., Zhu, L., Scarlett, Y., Magness, S., Brenner, D.
|
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<strong>Molecular defects in ferrochelatase in patients with protoporphyria requiring liver transplantation.</strong>
|
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J. Clin. Invest. 102: 107-114, 1998.
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[PubMed: 9649563]
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[Full Text: https://doi.org/10.1172/JCI1347]
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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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Bloomer, J. R.
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<strong>Characterization of deficient heme synthase activity in protoporphyria with cultured skin fibroblasts.</strong>
|
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J. Clin. Invest. 65: 321-328, 1980.
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[PubMed: 7356682]
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[Full Text: https://doi.org/10.1172/JCI109675]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bonkovsky, H. L., Schned, A. R.
|
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<strong>Fatal liver failure in protoporphyria: synergism between ethanol excess and the genetic defect.</strong>
|
|
Gastroenterology 90: 191-201, 1986.
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[PubMed: 3940245]
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</li>
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<li>
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<p class="mim-text-font">
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|
Bonkowsky, H. L., Bloomer, J. R., Ebert, P. S., Mahoney, M. J.
|
|
<strong>Heme synthetase deficiency in human protoporphyria: demonstration of the defect in liver and cultured skin fibroblasts.</strong>
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J. Clin. Invest. 56: 1139-1148, 1975.
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[PubMed: 1184741]
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[Full Text: https://doi.org/10.1172/JCI108189]
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</p>
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<li>
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<p class="mim-text-font">
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Brenner, D. A., Didier, J. M., Frasier, F., Christensen, S. R., Evans, G. A., Dailey, H. A.
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<strong>A molecular defect in human protoporphyria.</strong>
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Am. J. Hum. Genet. 50: 1203-1210, 1992.
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[PubMed: 1376018]
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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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Gouya, L., Martin-Schmitt, C., Robreau, A.-M., Austerlitz, F., Da Silva, V., Brun, P., Simonin, S., Lyoumi, S., Grandchamp, B., Beaumont, C., Puy, H., Deybach, J.-C.
|
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<strong>Contribution of a common single-nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria.</strong>
|
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Am. J. Hum. Genet. 78: 2-14, 2006.
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[PubMed: 16385445]
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[Full Text: https://doi.org/10.1086/498620]
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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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Gouya, L., Puy, H., Robreau, A.-M., Bourgeois, M., Lamoril, J., Da Silva, V., Grandchamp, B., Deybach, J.-C.
|
|
<strong>The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH.</strong>
|
|
Nature Genet. 30: 27-28, 2002.
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[PubMed: 11753383]
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[Full Text: https://doi.org/10.1038/ng809]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Gouya, L., Puy, H., Robreau, A.-M., Lyoumi, S., Lamoril, J., Da Silva, V., Grandchamp, B., Deybach, J.-C.
|
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<strong>Modulation of penetrance by the wild-type allele in dominantly inherited erythropoietic protoporphyria and acute hepatic porphyrias.</strong>
|
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Hum. Genet. 114: 256-262, 2004.
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[PubMed: 14669009]
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[Full Text: https://doi.org/10.1007/s00439-003-1059-5]
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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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Herrero, C., To-Figueras, J., Badenas, C., Mendez, M., Serrano, P., Enriquez-Salamanca, R., Lecha, M.
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<strong>Clinical, biochemical, and genetic study of 11 patients with erythropoietic protoporphyria including one with homozygous disease.</strong>
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Arch. Derm. 143: 1125-1129, 2007.
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[PubMed: 17875872]
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[Full Text: https://doi.org/10.1001/archderm.143.9.1125]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Inazawa, J., Taketani, S., Nakagawa, H., Inoue, K., Misawa, S., Abe, T.
|
|
<strong>Assignment of the human ferrochelatase gene (FCE) to chromosome 18 at region q21.3. (Abstract)</strong>
|
|
Cytogenet. Cell Genet. 58: 2014, 1991.
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Lamoril, J., Boulechfar, S., de Verneuil, H., Grandchamp, B., Nordmann, Y., Deybach, J.-C.
|
|
<strong>Human erythropoietic protoporphyria: two point mutations in the ferrochelatase gene.</strong>
|
|
Biochem. Biophys. Res. Commun. 181: 594-599, 1991.
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|
|
[PubMed: 1755842]
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[Full Text: https://doi.org/10.1016/0006-291x(91)91231-z]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Nakahashi, Y., Fujita, H., Taketani, S., Ishida, N., Kappas, A., Sassa, S.
|
|
<strong>The molecular defect of ferrochelatase in a patient with erythropoietic protoporphyria.</strong>
|
|
Proc. Nat. Acad. Sci. 89: 281-285, 1992.
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|
|
|
|
[PubMed: 1729699]
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|
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|
|
[Full Text: https://doi.org/10.1073/pnas.89.1.281]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Nakahashi, Y., Miyazaki, H., Kadota, Y., Naitoh, Y., Inoue, K., Yamamoto, M., Hayashi, N., Taketani, S.
|
|
<strong>Molecular defect in human erythropoietic protoporphyria with fatal liver failure.</strong>
|
|
Hum. Genet. 91: 303-306, 1993.
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|
|
|
|
|
[PubMed: 8500787]
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|
|
[Full Text: https://doi.org/10.1007/BF00217346]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Nakahashi, Y. N., Taketani, S. T., Okuda, M. O., Inoue, K. I., Tokunaga, R. T.
|
|
<strong>Molecular cloning and sequence analysis of cDNA encoding human ferrochelatase.</strong>
|
|
Biochem. Biophys. Res. Commun. 173: 748-755, 1990.
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|
|
[PubMed: 2260980]
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|
|
[Full Text: https://doi.org/10.1016/s0006-291x(05)80099-3]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Ohgari, Y., Sawamoto, M., Yamamoto, M., Kohno, H., Taketani, S.
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