5063 lines
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Entry
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- *600923 - PROTOPORPHYRINOGEN OXIDASE; PPOX
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- OMIM
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<p>
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<span class="h4">*600923</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600923">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div id="mimFloatingLinksMenu">
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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=ENSG00000143224;t=ENST00000367999" 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=5498" 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=600923" 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="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=ENSG00000143224;t=ENST00000367999" 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_000309,NM_001122764,NM_001350128,NM_001350129,NM_001350130,NM_001350131,NM_001365398,NM_001365399,NM_001365400,NM_001365401,XM_005245291,XM_005245295,XM_006711404,XM_011509663,XM_011509664,XM_011509665,XM_011509667,XM_011509668,XM_011509670,XM_011509671,XM_011509672,XM_011509673,XM_011509674,XM_011509678,XM_017001566,XM_024447864,XM_047423569,XM_047423581,XM_047423592,XM_047423604,XR_007061329" 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_001122764" 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=600923" 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=02953&isoform_id=02953_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/PPOX" 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/837328,854664,1709742,4009513,4506001,12004307,12004309,12803107,14009341,14009342,14582723,14582725,14582727,119573020,119573021,119573022,119573023,119573024,119573025,119573026,170650615,193787739,194379344,194386418,767909618,767909620,767909622,767909626,767909630,767909634,767909636,767909641,767909645,767909647,767909655,767909661,1034559507,1174098500,1174098502,1174098504,1174098506,1678214319,1678214321,1678214323,1678214325,2217268550,2217268554,2217268558,2217268561,2217268565,2217268567,2217268573,2462510567,2462510569,2462510571,2462510573,2462510575,2462510577,2462510579,2462510581,2462510583,2462510585,2462510587,2462510589,2462510591,2462510593,2462510595,2462510597,2462510599,2462510602,2462510604,2462510606,2462510609,2462510611" 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/P50336" 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=5498" 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=ENSG00000143224;t=ENST00000367999" 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=PPOX" 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=PPOX" 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+5498" 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/PPOX" 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:5498" 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/5498" 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=chr1&hgg_gene=ENST00000367999.9&hgg_start=161165728&hgg_end=161178013&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:9280" 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/ppox" 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=600923[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=600923[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/ENSG00000143224" 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=PPOX" 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=PPOX" 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=PPOX" 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=PPOX&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/PA33608" 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:9280" 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/FBgn0020018.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:104968" 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/PPOX#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:104968" 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/5498/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=5498" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-051120-90" 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">
|
|
<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:5498" 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=PPOX&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 58275005<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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600923
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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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PROTOPORPHYRINOGEN OXIDASE; PPOX
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</span>
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</h3>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PPOX" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PPOX</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">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/1/1341?start=-3&limit=10&highlight=1341">1q23.3</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:161165728-161178013&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'})">1:161,165,728-161,178,013</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>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
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Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=176200,620483" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
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>
|
|
</thead>
|
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<tbody>
|
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|
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<tr>
|
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<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/1341?start=-3&limit=10&highlight=1341">
|
|
1q23.3
|
|
</a>
|
|
</span>
|
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</td>
|
|
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|
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<td>
|
|
<span class="mim-font">
|
|
Variegate porphyria
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/176200"> 176200 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Variegate porphyria, childhood-onset
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/620483"> 620483 </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>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
|
</td>
|
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</tr>
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
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<p>Protoporphyrinogen oxidase (<a href="https://enzyme.expasy.org/EC/1.3.3.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 1.3.3.4</a>), the penultimate enzyme in the heme biosynthetic pathway, catalyzes the 6-electron oxidation of protoporphyrinogen IX to form protoporphyrin IX. The enzyme is located in the inner membrane of mitochondria from various tissues, including liver, lymphocytes, and cultured fibroblasts (summary by <a href="#16" class="mim-tip-reference" title="Nishimura, K., Taketani, S., Inokuchi, H. <strong>Cloning of a human cDNA for protoporphyrinogen oxidase by complementation in vivo of a hemG mutant of Escherichia coli.</strong> J. Biol. Chem. 270: 8076-8080, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7713909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7713909</a>] [<a href="https://doi.org/10.1074/jbc.270.14.8076" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7713909">Nishimura et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7713909" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#16" class="mim-tip-reference" title="Nishimura, K., Taketani, S., Inokuchi, H. <strong>Cloning of a human cDNA for protoporphyrinogen oxidase by complementation in vivo of a hemG mutant of Escherichia coli.</strong> J. Biol. Chem. 270: 8076-8080, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7713909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7713909</a>] [<a href="https://doi.org/10.1074/jbc.270.14.8076" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7713909">Nishimura et al. (1995)</a> cloned and characterized human PPOX cDNA and found that it consists of 477 amino acids with a molecular mass of 51 kD. The PPOX protein shows sequence similarity to the hemY gene of Bacillus subtilis. The N-terminal portion contains a conserved region that forms the dinucleotide-binding site seen in many flavin-containing proteins. Northern blot analysis detected a 1.8-kb mRNA in human K562 and HepG2 cells. When expressed in COS-1 monkey cells, the human PPOX cDNA produced much higher levels of PPOX activity, which was inhibited by acifluorfen, a specific inhibitor of PPOX. The human protein could also be detected in the mitochondria of the transfected cells despite the fact that the protein lacks the apparent transport-specific leader sequence seen in a number of other mitochondrial proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7713909" 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="#22" class="mim-tip-reference" title="Taketani, S., Inazawa, J., Abe, T., Furukawa, T., Kohno, H., Tokunaga, R., Nishimura, K., Inokuchi, H. <strong>The human protoporphyrinogen oxidase gene (PPOX): organization and location to chromosome 1.</strong> Genomics 29: 698-703, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8575762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8575762</a>] [<a href="https://doi.org/10.1006/geno.1995.9949" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8575762">Taketani et al. (1995)</a> demonstrated that the PPOX gene has 13 exons and spans about 8 kb. The exon/intron boundary sequences conformed to the consensus sequence. Primer extension analysis revealed 2 major transcriptional initiation sites in a region with sequence motifs characteristic of the promoter. The promoter region contains multiple Sp1 elements, CCAAT boxes, and potential GAT-1 binding sites. Mapping of the 5-prime end of PPOX mRNA by PCR indicated that the same transcripts exist in erythroid and nonerythroid cells. <a href="#19" class="mim-tip-reference" title="Puy, H., Robreau, A.-M., Rosipal, R., Nordmann, Y., Deybach, J.-C. <strong>Protoporphyrinogen oxidase: complete genomic sequence and polymorphisms in the human gene.</strong> Biochem. Biophys. Res. Commun. 226: 226-230, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8806618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8806618</a>] [<a href="https://doi.org/10.1006/bbrc.1996.1337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8806618">Puy et al. (1996)</a> confirmed the intron/exon structure of PPOX and reported its complete genomic DNA sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8575762+8806618" 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="#22" class="mim-tip-reference" title="Taketani, S., Inazawa, J., Abe, T., Furukawa, T., Kohno, H., Tokunaga, R., Nishimura, K., Inokuchi, H. <strong>The human protoporphyrinogen oxidase gene (PPOX): organization and location to chromosome 1.</strong> Genomics 29: 698-703, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8575762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8575762</a>] [<a href="https://doi.org/10.1006/geno.1995.9949" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8575762">Taketani et al. (1995)</a> showed by Southern blotting of human genomic DNA that there is a single copy of the PPOX gene, and by fluorescence in situ hybridization (FISH) they mapped the gene to 1q22. This represented a puzzling discrepancy with the mapping of VP to chromosome 14 by linkage. <a href="#22" class="mim-tip-reference" title="Taketani, S., Inazawa, J., Abe, T., Furukawa, T., Kohno, H., Tokunaga, R., Nishimura, K., Inokuchi, H. <strong>The human protoporphyrinogen oxidase gene (PPOX): organization and location to chromosome 1.</strong> Genomics 29: 698-703, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8575762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8575762</a>] [<a href="https://doi.org/10.1006/geno.1995.9949" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8575762">Taketani et al. (1995)</a> suggested that the product of a gene on chromosome 14 may interact with PPOX protein to maintain normal enzyme activity or to affect expression of the PPOX gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8575762" 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="Roberts, A. G., Whatley, S. D., Daniels, J., Holmans, P., Fenton, I., Owen, M. J., Thompson, P., Long, C., Elder, G. H. <strong>Partial characterization and assignment of the gene for protoporphyrinogen oxidase and variegate porphyria to human chromosome 1q23.</strong> Hum. Molec. Genet. 4: 2387-2390, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8634714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8634714</a>] [<a href="https://doi.org/10.1093/hmg/4.12.2387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8634714">Roberts et al. (1995)</a> mapped the PPOX gene to 1q23 by FISH; furthermore, they showed that variegate porphyria is linked to DNA markers in the 1q21-q25 region. They concluded that the findings spoke against locus heterogeneity in VP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8634714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#7" class="mim-tip-reference" title="Deybach, J.-C., Puy, H., Robreau, A.-M., Lamoril, J., Da Silva, V., Grandchamp, B., Nordmann, Y. <strong>Mutations in the protoporphyrinogen oxidase gene in patients with variegate porphyria.</strong> Hum. Molec. Genet. 5: 407-410, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8852667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8852667</a>] [<a href="https://doi.org/10.1093/hmg/5.3.407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8852667">Deybach et al. (1996)</a>, <a href="#14" class="mim-tip-reference" title="Meissner, P. N., Dailey, T. A., Hift, R. J., Ziman, M., Corrigall, A. V., Roberts, A. G., Meissner, D. M., Kirsch, R. E., Dailey, H. A. <strong>A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria.</strong> Nature Genet. 13: 95-97, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673113</a>] [<a href="https://doi.org/10.1038/ng0596-95" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673113">Meissner et al. (1996)</a>, <a href="#23" class="mim-tip-reference" title="Warnich, L., Kotze, M. J., Groenewald, I. M., Groenewald, J. Z., van Brakel, M. G., van Heerden, C. J., de Villiers, J. N. P., van de Ven, W. J. M., Schoenmakers, E. F. P. M., Taketani, S., Retief, A. E. <strong>Identification of three mutations and associated haplotypes in the protoporphyrinogen oxidase gene in South African families with variegate porphyria.</strong> Hum. Molec. Genet. 5: 981-984, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8817334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8817334</a>] [<a href="https://doi.org/10.1093/hmg/5.7.981" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8817334">Warnich et al. (1996)</a>, and <a href="#13" class="mim-tip-reference" title="Lam, H., Dragan, L., Tsou, H. C., Merk, H., Peacocke, M., Goerz, G., Sassa, S., Poh-Fitzpatrick, M., Bickers, D. R., Christiano, A. M. <strong>Molecular basis of variegate porphyria: a de novo insertion mutation in the protoporphyrinogen oxidase gene.</strong> Hum. Genet. 99: 126-129, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9003509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9003509</a>] [<a href="https://doi.org/10.1007/s004390050325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9003509">Lam et al. (1997)</a> identified heterozygous mutations in the PPOX gene (see, e.g., <a href="#0001">600923.0001</a>-<a href="#0005">600923.0005</a>) in patients with variegate porphyria (VP; <a href="/entry/176200">176200</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8817334+8852667+8673113+9003509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated women with variegate porphyria, <a href="#9" class="mim-tip-reference" title="Frank, J., Jugert, F. K., Breitkopf, C., Goerz, G., Merk, H. F., Christiano, A. M. <strong>Recurrent missense mutation in the protoporphyrinogen oxidase gene underlies variegate porphyria.</strong> Am. J. Med. Genet. 79: 22-26, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9738863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9738863</a>]" pmid="9738863">Frank et al. (1998)</a> identified heterozygosity for the same missense mutation (R168H; <a href="#0006">600923.0006</a>). Segregation analysis revealed that an unaffected son of one of the probands also carried the R168H variant, which was not found in controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9738863" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Wiman, A., Harper, P., Floderus, Y. <strong>Nine novel mutations in the protoporphyrinogen oxidase gene in Swedish families with variegate porphyria.</strong> Clin. Genet. 64: 122-130, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12859407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12859407</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00116.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12859407">Wiman et al. (2003)</a> stated that approximately 80 individuals from 28 apparently unrelated families had been diagnosed with VP in Sweden. Genetic analysis of the PPOX gene in 17 of these families identified 10 different mutations, only 1 of which had previously been reported. Mutation analysis in family members revealed 2 adults and 4 children who were silent carriers of the VP trait. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12859407" 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="Borrero Corte, M. J., Jara Rubio, F., Moran Jimenez, M. J., Diaz Diaz, S., Castelbon Fernandez, F. J., Garcia Pastor, I., Enriquez de Salamanca, R., Mendez, M. <strong>Molecular analysis of 19 Spanish patients with mixed porphyrias.</strong> Europ. J. Med. Genet. 62: 103589, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30476629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30476629</a>] [<a href="https://doi.org/10.1016/j.ejmg.2018.11.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30476629">Borrero Corte et al. (2019)</a> sequenced the PPOX gene in 8 unrelated Spanish patients with variegate porphyria, 4 of whom had only cutaneous photosensitivity, 3 of whom experienced only acute symptoms, and 1 of whom had both. The authors identified heterozygosity for known VP-associated mutations in all patients (see, e.g., <a href="#0006">600923.0006</a>). No genotype/phenotype correlations were observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30476629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Childhood-Onset Variegate Porphyria</em></strong></p><p>
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In an Afrikaner girl with photosensitivity, severe brachydactyly, seizures, developmental delay, sensory neuropathy, and an abnormal porphyrin excretion pattern (VPCO; <a href="/entry/620483">620483</a>), <a href="#14" class="mim-tip-reference" title="Meissner, P. N., Dailey, T. A., Hift, R. J., Ziman, M., Corrigall, A. V., Roberts, A. G., Meissner, D. M., Kirsch, R. E., Dailey, H. A. <strong>A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria.</strong> Nature Genet. 13: 95-97, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673113</a>] [<a href="https://doi.org/10.1038/ng0596-95" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673113">Meissner et al. (1996)</a> identified compound heterozygosity for missense mutations in the PPOX gene: an R59W substitution (<a href="#0003">600923.0003</a>) and an R168C substitution (<a href="#0004">600923.0004</a>). Her mother, who met the criteria for VP, was heterozygous for the R59W mutation, and her father, who had normal porphyrin biochemistry and a 25% reduction in PPO activity, was heterozygous for the R168C variant. The authors also detected the R59W mutation in 43 of 45 patients with autosomal dominant VP (<a href="/entry/176200">176200</a>) from 26 of 27 South African families; genealogic analysis of 1 of the South African families demonstrated relatedness to the original South African VP family tree, suggesting a founder effect. Functional analysis of the R59W mutation demonstrated that the mutant enzyme had an almost undetectable catalytic rate but a relatively invariant K(m), consistent with the 50% reduction in PPO activity seen in the proband's mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8673113" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 20-year-old woman with apparent autosomal recessive variegate porphyria, who in addition to cutaneous manifestations exhibited impaired intellectual development and hand deformities, <a href="#10" class="mim-tip-reference" title="Frank, J., McGrath, J., Lam, H., Graham, R. M., Hawk, J. L. M., Christiano, A. M. <strong>Homozygous variegate porphyria: identification of mutations on both alleles of the protoporphyrinogen oxidase gene in a severely affected proband.</strong> J. Invest. Derm. 110: 452-455, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9540991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9540991</a>] [<a href="https://doi.org/10.1046/j.1523-1747.1998.00148.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9540991">Frank et al. (1998)</a> identified compound heterozygosity for missense mutations in the PPOX gene: a G169E substitution (<a href="#0014">600923.0014</a>) and a G358R substitution (<a href="#0015">600923.0015</a>). Her asymptomatic parents, who both exhibited approximately half-normal levels of PPO activity, were each heterozygous for 1 of the mutations, neither of which was found in 50 unrelated controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9540991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Roberts, A. G., Puy, H., Dailey, T. A., Morgan, R. R., Whatley, S. D., Dailey, H. A., Martasek, P., Nordmann, Y., Deybach, J.-C., Elder, G. H. <strong>Molecular characterization of homozygous variegate porphyria.</strong> Hum. Molec. Genet. 7: 1921-1925, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9811936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9811936</a>] [<a href="https://doi.org/10.1093/hmg/7.12.1921" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9811936">Roberts et al. (1998)</a> confirmed the molecular characterization of the rare 'homozygous' variant of variegate porphyria. They identified PPOX mutations on both alleles of 5 of the 11 unrelated patients with apparent autosomal recessive VP reported to that time. Two patients were homozygous for missense mutations (D349A, <a href="#0007">600923.0007</a> and A433P), whereas 2 were compound heterozygous for a G358R substitution and either a G169E substitution or a splice site mutation, respectively, and the remaining patient was compound heterozygous for a 12-bp insertion and another splice site mutation. Functional analysis by prokaryotic expression showed that the D349A and A433P mutations and 1 missense mutation in each of the 3 heteroallelic patients (G538R in 2 patients and 657ins12) preserved some PPOX activity (9.5-25% of wildtype). Mutations on the other allele of the heteroallelic patients abolished or markedly decreased activity. There was no relation between genotype assessed by functional analysis and the presence or severity of noncutaneous manifestations. All the mutations found in the homozygous patients were absent from 104 unrelated patients with autosomal dominant VP. The authors concluded that mild PPOX mutations occur in the general population but have a very low or no clinical penetrance in heterozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9811936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 36-year-old British woman with severe cutaneous manifestations of variegate porphyria and brachydactyly, <a href="#18" class="mim-tip-reference" title="Palmer, R. A., Elder, G. H., Barrett, D. F., Keohane, S. G. <strong>Homozygous variegate porphyria: a compound heterozygote with novel mutations in the protoporphyrinogen oxidase gene.</strong> Brit. J. Derm. 144: 866-869, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11298551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11298551</a>] [<a href="https://doi.org/10.1046/j.1365-2133.2001.04147.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11298551">Palmer et al. (2001)</a> identified compound heterozygosity for mutations in the PPOX gene: an in-frame 12-bp insertion (<a href="#0010">600923.0010</a>) and a splice site mutation (<a href="#0011">600923.0011</a>). The proband's mother, who was heterozygous for the splice site mutation, experienced 3 neuroabdominal episodes, 2 of which followed drug ingestion; she had no cutaneous manifestations. A maternal first cousin, who also carried the splice site mutation, was asymptomatic. DNA was unavailable from the proband's deceased father, who was reported to be asymptomatic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11298551" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Finnish boy with apparent homozygous variegate porphyria, <a href="#12" class="mim-tip-reference" title="Kauppinen, R., Timonen, K., von und zu Fraunberg, M., Laitinen, E., Ahola, H., Tenhunen, R., Taketani, S., Mustajoki, P. <strong>Homozygous variegate porphyria: 20 y follow-up and characterization of molecular defect.</strong> J. Invest. Derm. 116: 610-613, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11286631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11286631</a>] [<a href="https://doi.org/10.1046/j.1523-1747.2001.01293.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11286631">Kauppinen et al. (2001)</a> identified compound heterozygosity for 2 missense mutations in the PPOX gene: an I12T substitution (<a href="#0012">600923.0012</a>) and a P256R substitution (<a href="#0013">600923.0013</a>). Affected members of another Finnish family were compound heterozygous for the same mutations, suggesting a common ancestor. One heterozygous carrier in each family was mildly symptomatic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11286631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 33-year-old Chinese man with childhood-onset variegate porphyria, <a href="#2" class="mim-tip-reference" title="Cho, S. Y., Lau, E. Y.-T., Luk, D. C.-K., Law, C.-Y., Lai, C.-K., Lam, C.-W. <strong>Novel PPOX exonic mutation inducing aberrant splicing in a patient with homozygous variegate porphyria.</strong> Clin. Chim. Acta 512: 117-120, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33159949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33159949</a>] [<a href="https://doi.org/10.1016/j.cca.2020.10.033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33159949">Cho et al. (2021)</a> sequenced the PPOX gene and identified homozygosity for a missense mutation (V270L; <a href="#0018">600923.0018</a>) at the first base of exon 8 of the PPOX gene. His unaffected consanguineous parents were heterozygous for the mutation. Functional analysis revealed that the mutation affected splicing, resulting in exon skipping that was predicted to result in a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33159949" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600923[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<p>In a patient (P1) of French Caucasian origin with variegate porphyria (VP; <a href="/entry/176200">176200</a>), <a href="#7" class="mim-tip-reference" title="Deybach, J.-C., Puy, H., Robreau, A.-M., Lamoril, J., Da Silva, V., Grandchamp, B., Nordmann, Y. <strong>Mutations in the protoporphyrinogen oxidase gene in patients with variegate porphyria.</strong> Hum. Molec. Genet. 5: 407-410, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8852667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8852667</a>] [<a href="https://doi.org/10.1093/hmg/5.3.407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8852667">Deybach et al. (1996)</a> identified heterozygosity for a 1-bp insertion (c.1022insG) in exon 7 of the PPOX gene, producing a frameshift that resulted in a premature stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8852667" 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 3 patients (P2-P4) from 2 unrelated French Caucasian families with variegate porphyria (VP; <a href="/entry/176200">176200</a>), <a href="#7" class="mim-tip-reference" title="Deybach, J.-C., Puy, H., Robreau, A.-M., Lamoril, J., Da Silva, V., Grandchamp, B., Nordmann, Y. <strong>Mutations in the protoporphyrinogen oxidase gene in patients with variegate porphyria.</strong> Hum. Molec. Genet. 5: 407-410, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8852667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8852667</a>] [<a href="https://doi.org/10.1093/hmg/5.3.407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8852667">Deybach et al. (1996)</a> found heterozygosity for a G-to-C transversion at nucleotide 971 (c.971G-C), resulting in a gly232-to-arg (G232R) substitution. In 1 of the families, consisting of 14 members over 3 generations, the authors demonstrated that the mutation segregated fully with deficient PPOX activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8852667" 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">rs121918324 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918324;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=rs121918324" 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=rs121918324" 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=RCV000009233 OR RCV001232723 OR RCV003324489" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009233, RCV001232723, RCV003324489" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009233...</a>
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<p>In a girl of Afrikaner origin with photosensitivity, severe brachydactyly, seizures, developmental delay, sensory neuropathy, and an abnormal porphyrin excretion pattern (VPCO; <a href="/entry/620483">620483</a>), who was originally described by <a href="#11" class="mim-tip-reference" title="Hift, R. J., Meissner, P. N., Todd, G., Kirby, P., Bilsland, D., Collins, P., Ferguson, J., Moore, M. R. <strong>Homozygous variegate porphyria: an evolving clinical syndrome.</strong> Postgrad. Med. J. 69: 781-786, 1993. Note: Erratum: Postgrad. Med. J. 70: 855 only, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8290408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8290408</a>] [<a href="https://doi.org/10.1136/pgmj.69.816.781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8290408">Hift et al. (1993)</a>, <a href="#14" class="mim-tip-reference" title="Meissner, P. N., Dailey, T. A., Hift, R. J., Ziman, M., Corrigall, A. V., Roberts, A. G., Meissner, D. M., Kirsch, R. E., Dailey, H. A. <strong>A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria.</strong> Nature Genet. 13: 95-97, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673113</a>] [<a href="https://doi.org/10.1038/ng0596-95" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673113">Meissner et al. (1996)</a> identified compound heterozygosity for missense mutations in the PPOX gene: a C-to-T transition in exon 3, resulting in an arg59-to-trp (R59W) substitution within the predicted FAD (see <a href="/entry/610595">610595</a>) dinucleotide-binding motif, and a C-to-T transition in codon 168, resulting in an arg168-to-cys (R168C; <a href="#0004">600923.0004</a>) substitution. The proband's mother, who met the criteria for autosomal dominant VP (<a href="/entry/176200">176200</a>), was heterozygous for the R59W mutation, and her father, who had normal porphyrin biochemistry and a 25% reduction in PPO activity, was heterozygous for the R168C variant. The authors also detected the R59W substitution in 43 of 45 patients with VP from 26 of 27 South African families, but not in 34 unaffected relatives or 9 unrelated British patients with PPO deficiency. Genealogic analysis of 1 of the South African families demonstrated relatedness to the original South African VP family tree (<a href="#6" class="mim-tip-reference" title="Dean, G. <strong>The Porphyrias. A Story of Inheritance and Environment.</strong> Philadelphia: J. B. Lippincott (pub.) 1972."None>Dean, 1972</a>), suggesting a founder effect. Functional analysis of the R59W mutation demonstrated that the mutant enzyme had an almost undetectable catalytic rate but a relatively invariant K(m), consistent with the reduced PPO activity seen in the VP patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8673113+8290408" 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="Warnich, L., Kotze, M. J., Groenewald, I. M., Groenewald, J. Z., van Brakel, M. G., van Heerden, C. J., de Villiers, J. N. P., van de Ven, W. J. M., Schoenmakers, E. F. P. M., Taketani, S., Retief, A. E. <strong>Identification of three mutations and associated haplotypes in the protoporphyrinogen oxidase gene in South African families with variegate porphyria.</strong> Hum. Molec. Genet. 5: 981-984, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8817334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8817334</a>] [<a href="https://doi.org/10.1093/hmg/5.7.981" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8817334">Warnich et al. (1996)</a> identified heterozygosity for the R59W mutation (c.452C-T) in 15 of 17 South African patients with variegate porphyria. This mutation was shown to create a StyI restriction site in the gene. It was also shown to be associated with C(26)-C(150), 1 of 4 potential haplotypes defined by 2 polymorphisms in exon 1 of the PPOX gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8817334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="de Villiers, J. N. P., Hillermann, R., Loubser, L., Kotze, M. J. <strong>Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria.</strong> Hum. Molec. Genet. 8: 1517-1522, 1999. Note: Erratum: Hum. Molec. Genet. 8: 1817 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10401000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10401000</a>] [<a href="https://doi.org/10.1093/hmg/8.8.1517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10401000">De Villiers et al. (1999)</a> identified a patient with severe variegate porphyria carrying the R59W allele of the PPOX gene who was also compound heterozygous for mutations in the HFE gene (Q127H, <a href="/entry/235200#0007">235200.0007</a> and H63D, <a href="/entry/235200#0002">235200.0002</a>). The authors also found that the mutant allele frequency of the HFE C282Y mutation (<a href="/entry/235200#0001">235200.0001</a>) was significantly lower in 73 apparently unrelated VP patients carrying the R59W mutation than in 102 controls drawn from the same population in South Africa (p = 0.005). The authors concluded that their findings supported data on the involvement of the HFE gene in the porphyria phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10401000" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 7-year-old girl of Afrikaner origin (family 1) with severe cutaneous photosensitivity, brachydactyly, and sensory neuropathy, <a href="#3" class="mim-tip-reference" title="Corrigall, A. V., Hift, R. J., Davids, L. M., Hancock, V., Meissner, D., Kirsch, R. E., Meissner, P. N. <strong>Homozygous variegate porphyria in South Africa: genotypic analysis in two cases.</strong> Molec. Genet. Metab. 69: 323-330, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10870850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10870850</a>] [<a href="https://doi.org/10.1006/mgme.2000.2975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10870850">Corrigall et al. (2000)</a> identified compound heterozygosity for the recurrent R59W mutation in the PPOX gene, and an A-to-G transition in exon 10, resulting in a tyr348-to-cys (Y348C; <a href="#0016">600923.0016</a>) substitution. Testing of 10 additional family members revealed heterozygosity for the R59W mutation in the proband's asymptomatic mother and 12-year-old sister; the mother showed a fecal porphyrin excretion pattern typical of VP, but the sister was biochemically negative. The proband's asymptomatic father, half brother, and half sister were heterozygous for the Y348C mutation; her father had a normal fecal porphyrin excretion profile but showed a small peak at 625 nm on plasma fluoroscanning, her half brother had a typical VP fecal porphyrin excretion pattern but normal plasma fluoroscan, and her half sister was biochemically negative. The Y348C mutation was shown to have arisen de novo in the father. In 2 South African sisters of mixed-race origin (family 2), 1 of whom experienced acute porphyric attacks and severe cutaneous photosensitivity and the other of whom showed typical VP skin disease, <a href="#3" class="mim-tip-reference" title="Corrigall, A. V., Hift, R. J., Davids, L. M., Hancock, V., Meissner, D., Kirsch, R. E., Meissner, P. N. <strong>Homozygous variegate porphyria in South Africa: genotypic analysis in two cases.</strong> Molec. Genet. Metab. 69: 323-330, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10870850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10870850</a>] [<a href="https://doi.org/10.1006/mgme.2000.2975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10870850">Corrigall et al. (2000)</a> identified compound heterozygosity for R59W in PPOX and a R138P mutation (<a href="#0017">600923.0017</a>). None of the mutations was found in 50 ethnically matched controls. Noting that the sisters who were compound heterozygous for the R59W and R138P mutations did not manifest symptoms in early childhood, the authors suggested that the R138P mutation might have more residual PPO activity than the Y438C mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10870850" 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> rs121918325 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918325;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/rs121918325?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=rs121918325" 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=rs121918325" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the C-to-T transition in codon 168 of the PPOX gene, resulting in an arg168-to-cys (R168C) substitution, that was found in compound heterozygous state in a girl of Afrikaner origin with childhood-onset variegate porphyria (VPCO; <a href="/entry/620483">620483</a>) by <a href="#14" class="mim-tip-reference" title="Meissner, P. N., Dailey, T. A., Hift, R. J., Ziman, M., Corrigall, A. V., Roberts, A. G., Meissner, D. M., Kirsch, R. E., Dailey, H. A. <strong>A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria.</strong> Nature Genet. 13: 95-97, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673113</a>] [<a href="https://doi.org/10.1038/ng0596-95" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673113">Meissner et al. (1996)</a>, see <a href="#0003">600923.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8673113" 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="Warnich, L., Kotze, M. J., Groenewald, I. M., Groenewald, J. Z., van Brakel, M. G., van Heerden, C. J., de Villiers, J. N. P., van de Ven, W. J. M., Schoenmakers, E. F. P. M., Taketani, S., Retief, A. E. <strong>Identification of three mutations and associated haplotypes in the protoporphyrinogen oxidase gene in South African families with variegate porphyria.</strong> Hum. Molec. Genet. 5: 981-984, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8817334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8817334</a>] [<a href="https://doi.org/10.1093/hmg/5.7.981" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8817334">Warnich et al. (1996)</a> identified heterozygosity for this exon 6 mutation (R168C) in the PPOX gene in 1 of 17 South African patients with variegate porphyria (VP; <a href="/entry/176200">176200</a>). This mutation would abolish a DsaI restriction site in genomic DNA of affected individuals, and was shown to be associated with a different haplotype for the exon 1 polymorphism A(26)-C(150) than were the R59W (<a href="#0003">600923.0003</a>) or H20P (<a href="#0005">600923.0005</a>) mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8817334" 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 1 of 17 unrelated patients with variegate porphyria (VP; <a href="/entry/176200">176200</a>) from South Africa, <a href="#23" class="mim-tip-reference" title="Warnich, L., Kotze, M. J., Groenewald, I. M., Groenewald, J. Z., van Brakel, M. G., van Heerden, C. J., de Villiers, J. N. P., van de Ven, W. J. M., Schoenmakers, E. F. P. M., Taketani, S., Retief, A. E. <strong>Identification of three mutations and associated haplotypes in the protoporphyrinogen oxidase gene in South African families with variegate porphyria.</strong> Hum. Molec. Genet. 5: 981-984, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8817334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8817334</a>] [<a href="https://doi.org/10.1093/hmg/5.7.981" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8817334">Warnich et al. (1996)</a> identified heterozygosity for a c.336A-C transversion in exon 2 of the PPOX gene that resulted in a his20-to-pro (H20P) amino acid substitution. The mutation was associated with the same exon 1 polymorphism haplotype as the R59W mutation (<a href="#0003">600923.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8817334" 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">rs41270025 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs41270025;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=rs41270025" 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=rs41270025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 57-year-old woman (proband 1) and an unrelated 38-year-old woman (proband 2) with variegate porphyria (VP; <a href="/entry/176200">176200</a>), <a href="#9" class="mim-tip-reference" title="Frank, J., Jugert, F. K., Breitkopf, C., Goerz, G., Merk, H. F., Christiano, A. M. <strong>Recurrent missense mutation in the protoporphyrinogen oxidase gene underlies variegate porphyria.</strong> Am. J. Med. Genet. 79: 22-26, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9738863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9738863</a>]" pmid="9738863">Frank et al. (1998)</a> identified a c.502G-A transition in exon 6 of the PPOX gene, resulting in an arg168-to-his (R168H) substitution at a highly conserved residue. The mutation occurred in the same codon as the previously reported arg168-to-cys mutation (R168C; <a href="#0004">600923.0004</a>) and, noting that the mutation involved a putatively hypermutable CpG dinucleotide, the authors suggested that R168 might be a mutational hotspot. Segregation analysis in the family of proband 1 revealed that her unaffected son also carried the R168H variant, indicating incomplete penetrance; relatives of proband 2 were unavailable for study. The mutation was not found in 50 unrelated controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9738863" 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="Frank, J., Aita, V. M., Ahmad, W., Lam, H., Wolff, C., Christiano, A. M. <strong>Identification of a founder mutation in the protoporphyrinogen oxidase gene in variegate porphyria patients from Chile.</strong> Hum. Hered. 51: 160-168, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11173967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11173967</a>] [<a href="https://doi.org/10.1159/000053337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11173967">Frank et al. (2001)</a> found the same R168H mutation on separate haplotypes in 6 VP patients from 3 unrelated families in Chile. The authors suggested that R168H is a hotspot mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11173967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated Spanish women with VP, including an 18-year-old (patient 2) with only cutaneous photosensitivity and a 64-year-old (patient 3) with only acute symptoms, <a href="#1" class="mim-tip-reference" title="Borrero Corte, M. J., Jara Rubio, F., Moran Jimenez, M. J., Diaz Diaz, S., Castelbon Fernandez, F. J., Garcia Pastor, I., Enriquez de Salamanca, R., Mendez, M. <strong>Molecular analysis of 19 Spanish patients with mixed porphyrias.</strong> Europ. J. Med. Genet. 62: 103589, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30476629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30476629</a>] [<a href="https://doi.org/10.1016/j.ejmg.2018.11.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30476629">Borrero Corte et al. (2019)</a> identified heterozygosity for the previously reported R168H mutation in the PPOX gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30476629" 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">rs28936676 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28936676;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=rs28936676" 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=rs28936676" 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=RCV003324490" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003324490" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003324490</a>
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<p>In a boy (patient 3) with childhood-onset variegate porphyria (VPCO; <a href="/entry/620483">620483</a>), <a href="#20" class="mim-tip-reference" title="Roberts, A. G., Puy, H., Dailey, T. A., Morgan, R. R., Whatley, S. D., Dailey, H. A., Martasek, P., Nordmann, Y., Deybach, J.-C., Elder, G. H. <strong>Molecular characterization of homozygous variegate porphyria.</strong> Hum. Molec. Genet. 7: 1921-1925, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9811936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9811936</a>] [<a href="https://doi.org/10.1093/hmg/7.12.1921" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9811936">Roberts et al. (1998)</a> found homozygosity for a c.1046A-C transversion in exon 10 of the PPOX gene, resulting in an asp349-to-ala (D349A) substitution. The patient, a 16-year-old male at the time of study, was the offspring of consanguineous Lebanese parents and had developed severe skin lesions from the age of 8 months. The diagnosis of homozygous VP was made at the age of 7 years. The patient had no mental retardation, convulsions, nystagmus, or growth retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9811936" 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">rs1571357779 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1571357779;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=rs1571357779" 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=rs1571357779" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 31-year-old South African woman of mixed racial ancestry with variegate porphyria (VP; <a href="/entry/176200">176200</a>), <a href="#4" class="mim-tip-reference" title="Corrigall, A. V., Hift, R. J., Hancock, V., Meissner, D., Davids, L., Kirsch, R. E., Meissner, P. N. <strong>Identification and characterisation of a deletion (537delAT) in the protoporphyrinogen oxidase gene in a South African variegate porphyria family.</strong> Hum. Mutat. 12: 403-407, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9829909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9829909</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)12:6<403::AID-HUMU6>3.0.CO;2-X" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9829909">Corrigall et al. (1998)</a> identified a heterozygous 2-bp deletion in exon 6, c.537delAT, which resulted in a premature stop codon 11 codons downstream. The mutation was also found in her affected cousin. Among 31 family members tested, 17 were found to carry the mutation; 13 of these 17 showed biochemical evidence of VP in urine and stool porphyrin analysis, whereas the other 4 had normal porphyrin excretion patterns. Only 3 of the 17 were symptomatic. This rare variant was the first reported deletion in the PPOX gene in a South African family. <a href="#4" class="mim-tip-reference" title="Corrigall, A. V., Hift, R. J., Hancock, V., Meissner, D., Davids, L., Kirsch, R. E., Meissner, P. N. <strong>Identification and characterisation of a deletion (537delAT) in the protoporphyrinogen oxidase gene in a South African variegate porphyria family.</strong> Hum. Mutat. 12: 403-407, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9829909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9829909</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)12:6<403::AID-HUMU6>3.0.CO;2-X" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9829909">Corrigall et al. (1998)</a> noted that the great majority of South African patients with VP carry the R59W mutation of the PPOX gene (<a href="#0003">600923.0003</a>). H20P (<a href="#0005">600923.0005</a>) and R168C (<a href="#0004">600923.0004</a>) are uncommon mutations in South African families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9829909" 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">rs2101902523 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2101902523;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=rs2101902523" 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=rs2101902523" 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=RCV000009237" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009237" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009237</a>
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<p><a href="#8" class="mim-tip-reference" title="Frank, J., Aita, V. M., Ahmad, W., Lam, H., Wolff, C., Christiano, A. M. <strong>Identification of a founder mutation in the protoporphyrinogen oxidase gene in variegate porphyria patients from Chile.</strong> Hum. Hered. 51: 160-168, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11173967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11173967</a>] [<a href="https://doi.org/10.1159/000053337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11173967">Frank et al. (2001)</a> found an apparent founder mutation, c.1239delTACAC, on the same chromosome 1 haplotype in 11 mutation carriers from 4 Chilean families with variegate porphyria (VP; <a href="/entry/176200">176200</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11173967" 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">rs2101876868 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2101876868;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=rs2101876868" 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=rs2101876868" 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=RCV003324491" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003324491" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003324491</a>
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<p>In a 36-year-old British woman with severe cutaneous manifestations of variegate porphyria and brachydactyly (VPCO; <a href="/entry/620483">620483</a>), <a href="#18" class="mim-tip-reference" title="Palmer, R. A., Elder, G. H., Barrett, D. F., Keohane, S. G. <strong>Homozygous variegate porphyria: a compound heterozygote with novel mutations in the protoporphyrinogen oxidase gene.</strong> Brit. J. Derm. 144: 866-869, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11298551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11298551</a>] [<a href="https://doi.org/10.1046/j.1365-2133.2001.04147.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11298551">Palmer et al. (2001)</a> identified compound heterozygosity for mutations in the PPOX gene: an in-frame 12-bp insertion (c.657-658insAAGGCCAGCGCC), encoding 4 additional amino acid residues (KASA), and a splice site mutation at the donor site of exon 11 (IVS11-1G-A; <a href="#0011">600923.0011</a>). The proband's mother, who was heterozygous for the splice site mutation, experienced 3 neuroabdominal episodes, 2 of which followed drug ingestion (VP; <a href="/entry/176200">176200</a>); she had no cutaneous manifestations. A maternal first cousin, who also carried the splice site mutation, was asymptomatic. DNA was unavailable from the proband's deceased father, who was reported to be asymptomatic. The patient had onset of skin fragility, scarring, and blisters on sun-exposed sites at 9 months of age. She experienced a febrile convulsion at 4 years of age, had delayed bone age at 19 years of age, and was of short stature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11298551" 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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VARIEGATE PORPHYRIA, INCLUDED
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003324492 OR RCV003324493" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003324492, RCV003324493" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003324492...</a>
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<p>For a discussion of the IVS11-1G-A mutation in the PPOX gene that was found in compound heterozygous state in a woman with childhood-onset variegate porphyria (VPCO; <a href="/entry/620483">620483</a>) by <a href="#18" class="mim-tip-reference" title="Palmer, R. A., Elder, G. H., Barrett, D. F., Keohane, S. G. <strong>Homozygous variegate porphyria: a compound heterozygote with novel mutations in the protoporphyrinogen oxidase gene.</strong> Brit. J. Derm. 144: 866-869, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11298551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11298551</a>] [<a href="https://doi.org/10.1046/j.1365-2133.2001.04147.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11298551">Palmer et al. (2001)</a>, see <a href="#0010">600923.0010</a>. The mutation had been transmitted by her mother, who had experienced 3 neuroabdominal porphyric episodes, 2 of which followed drug ingestion (VP; <a href="/entry/176200">176200</a>); she had no cutaneous manifestations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11298551" 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 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</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> rs28936677 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28936677;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/rs28936677?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=rs28936677" 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=rs28936677" 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=RCV003324494 OR RCV003324495" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003324494, RCV003324495" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003324494...</a>
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<p>In a Finnish boy with childhood-onset variegate porphyria (VPCO; <a href="/entry/620483">620483</a>), originally described by <a href="#15" class="mim-tip-reference" title="Mustajoki, P., Tenhunen, R., Niemi, K. M., Nordmann, Y., Kaariainen, H., Norio, R. <strong>Homozygous variegate porphyria: a severe skin disease of infancy.</strong> Clin. Genet. 32: 300-305, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3319294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3319294</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1987.tb03294.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3319294">Mustajoki et al. (1987)</a>, <a href="#12" class="mim-tip-reference" title="Kauppinen, R., Timonen, K., von und zu Fraunberg, M., Laitinen, E., Ahola, H., Tenhunen, R., Taketani, S., Mustajoki, P. <strong>Homozygous variegate porphyria: 20 y follow-up and characterization of molecular defect.</strong> J. Invest. Derm. 116: 610-613, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11286631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11286631</a>] [<a href="https://doi.org/10.1046/j.1523-1747.2001.01293.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11286631">Kauppinen et al. (2001)</a> identified compound heterozygosity for mutations in the PPOX gene: a c.35T-C transition in exon 2 of the PPOX gene, resulting in an ile12-to-thr (I12T) substitution, and a c.767C-G transversion in exon 7, resulting in a pro256-to-arg (P256R; <a href="#0013">600923.0013</a>) substitution. His asymptomatic first-cousin parents and his grandmothers were heterozygous for the mutations. <a href="#15" class="mim-tip-reference" title="Mustajoki, P., Tenhunen, R., Niemi, K. M., Nordmann, Y., Kaariainen, H., Norio, R. <strong>Homozygous variegate porphyria: a severe skin disease of infancy.</strong> Clin. Genet. 32: 300-305, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3319294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3319294</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1987.tb03294.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3319294">Mustajoki et al. (1987)</a> reported that 1 of the grandmothers was mildly affected, experiencing blistering on exposed skin in the summer with residual scarring. Affected members of another Finnish family were compound heterozygous for the same mutations, suggesting a common ancestor. <a href="#12" class="mim-tip-reference" title="Kauppinen, R., Timonen, K., von und zu Fraunberg, M., Laitinen, E., Ahola, H., Tenhunen, R., Taketani, S., Mustajoki, P. <strong>Homozygous variegate porphyria: 20 y follow-up and characterization of molecular defect.</strong> J. Invest. Derm. 116: 610-613, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11286631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11286631</a>] [<a href="https://doi.org/10.1046/j.1523-1747.2001.01293.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11286631">Kauppinen et al. (2001)</a> noted that 1 heterozygous carrier of the I12T mutation in the second Finnish family had experienced 2 acute attacks in her youth associated with sulfonamides. Expression of the mutant enzymes in E. coli and COS-1 cells showed that the I12T mutation resulted in loss of enzyme function, whereas the P256R mutation resulted in less than half of normal PPOX activity in the prokaryotic system and almost normal activity in the eukaryotic cells. <a href="#12" class="mim-tip-reference" title="Kauppinen, R., Timonen, K., von und zu Fraunberg, M., Laitinen, E., Ahola, H., Tenhunen, R., Taketani, S., Mustajoki, P. <strong>Homozygous variegate porphyria: 20 y follow-up and characterization of molecular defect.</strong> J. Invest. Derm. 116: 610-613, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11286631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11286631</a>] [<a href="https://doi.org/10.1046/j.1523-1747.2001.01293.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11286631">Kauppinen et al. (2001)</a> noted that the P256R change had been identified as a polymorphism in western European populations (<a href="#24" class="mim-tip-reference" title="Whatley, S. D., Puy, H., Morgan, R. R., Robreau, A.-M., Roberts, A. G., Nordmann, Y., Elder, G. H., Deybach, J.-C. <strong>Variegate porphyria in Western Europe: identification of PPOX gene mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation.</strong> Am. J. Hum. Genet. 65: 984-994, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10486317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10486317</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10486317[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/10.1086/302586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10486317">Whatley et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10486317+3319294+11286631" 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> rs12735723 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12735723;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/rs12735723?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=rs12735723" 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=rs12735723" 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=RCV000961007 OR RCV000986448 OR RCV003324496 OR RCV003924820" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000961007, RCV000986448, RCV003324496, RCV003924820" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000961007...</a>
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<p>For discussion of the c.767C-G transition in exon 7 of the PPOX gene, resulting in a pro256-to-arg (P256R) substitution, that was found in compound heterozygous state in affected members of 2 Finnish families with childhood-onset variegate porphyria (VPCO; <a href="/entry/620483">620483</a>) by <a href="#12" class="mim-tip-reference" title="Kauppinen, R., Timonen, K., von und zu Fraunberg, M., Laitinen, E., Ahola, H., Tenhunen, R., Taketani, S., Mustajoki, P. <strong>Homozygous variegate porphyria: 20 y follow-up and characterization of molecular defect.</strong> J. Invest. Derm. 116: 610-613, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11286631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11286631</a>] [<a href="https://doi.org/10.1046/j.1523-1747.2001.01293.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11286631">Kauppinen et al. (2001)</a>, see <a href="#0012">600923.0012</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11286631" 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 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003324652" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003324652" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003324652</a>
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<p>In a 20-year-old woman with childhood-onset variegate porphyria (VPCO; <a href="/entry/620483">620483</a>), originally described by <a href="#17" class="mim-tip-reference" title="Norris, P. G., Elder, G. H., Hawk, J. L. M. <strong>Homozygous variegate porphyria: a case report.</strong> Brit. J. Derm. 122: 253-257, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2317449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2317449</a>] [<a href="https://doi.org/10.1111/j.1365-2133.1990.tb08272.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2317449">Norris et al. (1990)</a>, who in addition to cutaneous manifestations exhibited impaired intellectual development and hand deformities, <a href="#10" class="mim-tip-reference" title="Frank, J., McGrath, J., Lam, H., Graham, R. M., Hawk, J. L. M., Christiano, A. M. <strong>Homozygous variegate porphyria: identification of mutations on both alleles of the protoporphyrinogen oxidase gene in a severely affected proband.</strong> J. Invest. Derm. 110: 452-455, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9540991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9540991</a>] [<a href="https://doi.org/10.1046/j.1523-1747.1998.00148.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9540991">Frank et al. (1998)</a> identified compound heterozygosity for missense mutations in the PPOX gene: a c.505G-A transition in exon 6, resulting in a gly169-to-glu (G169E) substitution at a highly conserved residue, and a c.1071G-A transition in exon 10, resulting in a gly358-to-arg (G358R; <a href="#0015">600923.0015</a>) substitution at a conserved residue. Her asymptomatic parents were each heterozygous for 1 of the mutations, neither of which was found in 50 unrelated controls. <a href="#10" class="mim-tip-reference" title="Frank, J., McGrath, J., Lam, H., Graham, R. M., Hawk, J. L. M., Christiano, A. M. <strong>Homozygous variegate porphyria: identification of mutations on both alleles of the protoporphyrinogen oxidase gene in a severely affected proband.</strong> J. Invest. Derm. 110: 452-455, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9540991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9540991</a>] [<a href="https://doi.org/10.1046/j.1523-1747.1998.00148.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9540991">Frank et al. (1998)</a> noted that the patient had PPO activity that was less than 20% of normal, whereas both parents had approximately half-normal levels of PPO activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9540991+2317449" 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 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</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> rs374936130 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs374936130;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/rs374936130?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=rs374936130" 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=rs374936130" 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=RCV001169976 OR RCV001339128 OR RCV003328475" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001169976, RCV001339128, RCV003328475" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001169976...</a>
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<p>For discussion of the c.1071G-A transition in exon 10 of the PPOX gene, resulting in a gly358-to-arg (G358R) substitution, that was found in compound heterozygous state in a 20-year-old woman with childhood-onset variegate porphyria (VPCO; <a href="/entry/620483">620483</a>) by <a href="#10" class="mim-tip-reference" title="Frank, J., McGrath, J., Lam, H., Graham, R. M., Hawk, J. L. M., Christiano, A. M. <strong>Homozygous variegate porphyria: identification of mutations on both alleles of the protoporphyrinogen oxidase gene in a severely affected proband.</strong> J. Invest. Derm. 110: 452-455, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9540991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9540991</a>] [<a href="https://doi.org/10.1046/j.1523-1747.1998.00148.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9540991">Frank et al. (1998)</a>, see <a href="#0014">600923.0014</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9540991" 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 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</strong>
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PPOX, TYR348CYS
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003324654" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003324654" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003324654</a>
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<p>For discussion of the A-to-G transition in exon 10 of the PPOX gene, resulting in a tyr348-to-cys (Y348C) substitution, that was found in compound heterozygous state in a 7-year-old girl of Afrikaner origin (family 1) with childhood-onset variegate porphyria (VPCO; <a href="/entry/620483">620483</a>) by <a href="#3" class="mim-tip-reference" title="Corrigall, A. V., Hift, R. J., Davids, L. M., Hancock, V., Meissner, D., Kirsch, R. E., Meissner, P. N. <strong>Homozygous variegate porphyria in South Africa: genotypic analysis in two cases.</strong> Molec. Genet. Metab. 69: 323-330, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10870850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10870850</a>] [<a href="https://doi.org/10.1006/mgme.2000.2975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10870850">Corrigall et al. (2000)</a>, see <a href="#0003">600923.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10870850" 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>.0017 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</strong>
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PPOX, ARG138PRO
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003324655" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003324655" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003324655</a>
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<p>For discussion of the G-to-C transversion in exon 5 of the PPOX gene, resulting in an arg138-to-pro (R138P) substitution, that was found in compound heterozygous state in 2 South African sisters of mixed-race origin (family 2) with childhood-onset variegate porphyria (VPCO; <a href="/entry/620483">620483</a>) by <a href="#3" class="mim-tip-reference" title="Corrigall, A. V., Hift, R. J., Davids, L. M., Hancock, V., Meissner, D., Kirsch, R. E., Meissner, P. N. <strong>Homozygous variegate porphyria in South Africa: genotypic analysis in two cases.</strong> Molec. Genet. Metab. 69: 323-330, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10870850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10870850</a>] [<a href="https://doi.org/10.1006/mgme.2000.2975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10870850">Corrigall et al. (2000)</a>, see <a href="#0003">600923.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10870850" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0018" class="mim-anchor"></a>
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<strong>.0018 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</strong>
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PPOX, VAL270LEU
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003324656" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003324656" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003324656</a>
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<p>In a 33-year-old Chinese man with childhood-onset variegate porphyria (VRCO; <a href="/entry/620483">620483</a>), <a href="#2" class="mim-tip-reference" title="Cho, S. Y., Lau, E. Y.-T., Luk, D. C.-K., Law, C.-Y., Lai, C.-K., Lam, C.-W. <strong>Novel PPOX exonic mutation inducing aberrant splicing in a patient with homozygous variegate porphyria.</strong> Clin. Chim. Acta 512: 117-120, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33159949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33159949</a>] [<a href="https://doi.org/10.1016/j.cca.2020.10.033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33159949">Cho et al. (2021)</a> identified homozygosity for a c.808G-T transversion (c.808G-T, NM_000309.3) at the first base of exon 8 in the PPOX gene, resulting in a val270-to-leu (V270L) substitution. His unaffected consanguineous parents were heterozygous for the mutation, which was not found in the gnomAD v.2.1.1 database. Functional analysis in transfected HEK293 cells revealed only a 200-bp band similar to the vector-only control, with absence of the normal 300-bp product, suggesting aberrant splicing. Sanger sequencing confirmed skipping of exon 8, causing a frameshift predicted to result in a premature termination codon (Val270CysfsTer17). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33159949" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="references"class="mim-anchor"></a>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="Borrero Corte2019" class="mim-anchor"></a>
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Borrero Corte, M. J., Jara Rubio, F., Moran Jimenez, M. J., Diaz Diaz, S., Castelbon Fernandez, F. J., Garcia Pastor, I., Enriquez de Salamanca, R., Mendez, M.
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<strong>Molecular analysis of 19 Spanish patients with mixed porphyrias.</strong>
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Europ. J. Med. Genet. 62: 103589, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30476629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30476629</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30476629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ejmg.2018.11.023" target="_blank">Full Text</a>]
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<a id="Cho2021" class="mim-anchor"></a>
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Cho, S. Y., Lau, E. Y.-T., Luk, D. C.-K., Law, C.-Y., Lai, C.-K., Lam, C.-W.
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<strong>Novel PPOX exonic mutation inducing aberrant splicing in a patient with homozygous variegate porphyria.</strong>
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Clin. Chim. Acta 512: 117-120, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33159949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33159949</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33159949" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.cca.2020.10.033" target="_blank">Full Text</a>]
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<a id="Corrigall2000" class="mim-anchor"></a>
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Corrigall, A. V., Hift, R. J., Davids, L. M., Hancock, V., Meissner, D., Kirsch, R. E., Meissner, P. N.
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<strong>Homozygous variegate porphyria in South Africa: genotypic analysis in two cases.</strong>
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Molec. Genet. Metab. 69: 323-330, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10870850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10870850</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10870850" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/mgme.2000.2975" target="_blank">Full Text</a>]
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<a id="Corrigall1998" class="mim-anchor"></a>
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Corrigall, A. V., Hift, R. J., Hancock, V., Meissner, D., Davids, L., Kirsch, R. E., Meissner, P. N.
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<strong>Identification and characterisation of a deletion (537delAT) in the protoporphyrinogen oxidase gene in a South African variegate porphyria family.</strong>
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Hum. Mutat. 12: 403-407, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9829909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9829909</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9829909" 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/10.1002/(SICI)1098-1004(1998)12:6<403::AID-HUMU6>3.0.CO;2-X" target="_blank">Full Text</a>]
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de Villiers, J. N. P., Hillermann, R., Loubser, L., Kotze, M. J.
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<strong>Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria.</strong>
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Hum. Molec. Genet. 8: 1517-1522, 1999. Note: Erratum: Hum. Molec. Genet. 8: 1817 only, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10401000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10401000</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10401000" 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/10.1093/hmg/8.8.1517" target="_blank">Full Text</a>]
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<a id="Dean1972" class="mim-anchor"></a>
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Dean, G.
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<strong>The Porphyrias. A Story of Inheritance and Environment.</strong>
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Philadelphia: J. B. Lippincott (pub.) 1972.
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<a id="Deybach1996" class="mim-anchor"></a>
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Deybach, J.-C., Puy, H., Robreau, A.-M., Lamoril, J., Da Silva, V., Grandchamp, B., Nordmann, Y.
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<strong>Mutations in the protoporphyrinogen oxidase gene in patients with variegate porphyria.</strong>
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Hum. Molec. Genet. 5: 407-410, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8852667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8852667</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8852667" 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/10.1093/hmg/5.3.407" target="_blank">Full Text</a>]
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<a id="Frank2001" class="mim-anchor"></a>
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Frank, J., Aita, V. M., Ahmad, W., Lam, H., Wolff, C., Christiano, A. M.
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<strong>Identification of a founder mutation in the protoporphyrinogen oxidase gene in variegate porphyria patients from Chile.</strong>
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Hum. Hered. 51: 160-168, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11173967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11173967</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11173967" 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/10.1159/000053337" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1046/j.1523-1747.1998.00148.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/pgmj.69.816.781" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s004390050325" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12859407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12859407</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12859407" 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/10.1034/j.1399-0004.2003.00116.x" 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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Marla J. F. O'Neill - updated : 09/11/2023
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 08/25/2023<br>Victor A. McKusick - updated : 6/10/2004<br>Cassandra L. Kniffin - updated : 6/3/2004<br>Victor A. McKusick - updated : 8/20/2003<br>Gary A. Bellus - updated : 4/29/2003<br>Victor A. McKusick - updated : 4/6/2001<br>Ada Hamosh - updated : 8/9/1999<br>Victor A. McKusick - updated : 12/2/1998<br>Victor A. McKusick - updated : 11/10/1998<br>Victor A. McKusick - updated : 9/16/1998<br>Jennifer P. Macke - updated : 7/11/1997<br>Moyra Smith - updated : 8/20/1996
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 11/7/1995
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </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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carol : 09/29/2023
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alopez : 09/11/2023<br>alopez : 09/11/2023<br>alopez : 08/25/2023<br>alopez : 08/25/2023<br>carol : 08/23/2023<br>carol : 05/29/2019<br>alopez : 04/03/2017<br>carol : 07/09/2016<br>carol : 8/17/2015<br>mcolton : 8/12/2015<br>carol : 4/12/2013<br>terry : 6/6/2012<br>joanna : 11/15/2010<br>carol : 8/5/2010<br>carol : 8/5/2010<br>terry : 2/2/2005<br>carol : 6/10/2004<br>carol : 6/7/2004<br>ckniffin : 6/3/2004<br>ckniffin : 6/3/2004<br>tkritzer : 8/25/2003<br>terry : 8/20/2003<br>alopez : 4/29/2003<br>mgross : 10/17/2001<br>mcapotos : 4/11/2001<br>mcapotos : 4/6/2001<br>terry : 4/6/2001<br>alopez : 8/17/1999<br>terry : 8/9/1999<br>dkim : 12/14/1998<br>carol : 12/9/1998<br>terry : 12/2/1998<br>carol : 11/13/1998<br>terry : 11/10/1998<br>alopez : 9/17/1998<br>terry : 9/16/1998<br>carol : 7/6/1998<br>jenny : 9/2/1997<br>jenny : 8/13/1997<br>jenny : 1/10/1997<br>terry : 12/30/1996<br>terry : 8/20/1996<br>terry : 8/20/1996<br>terry : 5/2/1996<br>mark : 4/30/1996<br>mark : 4/30/1996<br>terry : 4/30/1996<br>terry : 11/7/1995
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<span class="mim-font">
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<strong>*</strong> 600923
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<div>
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<h3>
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<span class="mim-font">
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PROTOPORPHYRINOGEN OXIDASE; PPOX
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: PPOX</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 58275005;
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<strong>
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<em>
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Cytogenetic location: 1q23.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:161,165,728-161,178,013 </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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<strong>Gene-Phenotype Relationships</strong>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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</th>
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<td rowspan="2">
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<span class="mim-font">
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1q23.3
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<span class="mim-font">
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Variegate porphyria
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<span class="mim-font">
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176200
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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Variegate porphyria, childhood-onset
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<span class="mim-font">
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620483
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<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>Protoporphyrinogen oxidase (EC 1.3.3.4), the penultimate enzyme in the heme biosynthetic pathway, catalyzes the 6-electron oxidation of protoporphyrinogen IX to form protoporphyrin IX. The enzyme is located in the inner membrane of mitochondria from various tissues, including liver, lymphocytes, and cultured fibroblasts (summary by Nishimura et al., 1995). </p>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</h4>
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<span class="mim-text-font">
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<p>Nishimura et al. (1995) cloned and characterized human PPOX cDNA and found that it consists of 477 amino acids with a molecular mass of 51 kD. The PPOX protein shows sequence similarity to the hemY gene of Bacillus subtilis. The N-terminal portion contains a conserved region that forms the dinucleotide-binding site seen in many flavin-containing proteins. Northern blot analysis detected a 1.8-kb mRNA in human K562 and HepG2 cells. When expressed in COS-1 monkey cells, the human PPOX cDNA produced much higher levels of PPOX activity, which was inhibited by acifluorfen, a specific inhibitor of PPOX. The human protein could also be detected in the mitochondria of the transfected cells despite the fact that the protein lacks the apparent transport-specific leader sequence seen in a number of other mitochondrial proteins. </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 Structure</strong>
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</h4>
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<span class="mim-text-font">
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<p>Taketani et al. (1995) demonstrated that the PPOX gene has 13 exons and spans about 8 kb. The exon/intron boundary sequences conformed to the consensus sequence. Primer extension analysis revealed 2 major transcriptional initiation sites in a region with sequence motifs characteristic of the promoter. The promoter region contains multiple Sp1 elements, CCAAT boxes, and potential GAT-1 binding sites. Mapping of the 5-prime end of PPOX mRNA by PCR indicated that the same transcripts exist in erythroid and nonerythroid cells. Puy et al. (1996) confirmed the intron/exon structure of PPOX and reported its complete genomic DNA sequence. </p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Taketani et al. (1995) showed by Southern blotting of human genomic DNA that there is a single copy of the PPOX gene, and by fluorescence in situ hybridization (FISH) they mapped the gene to 1q22. This represented a puzzling discrepancy with the mapping of VP to chromosome 14 by linkage. Taketani et al. (1995) suggested that the product of a gene on chromosome 14 may interact with PPOX protein to maintain normal enzyme activity or to affect expression of the PPOX gene. </p><p>Roberts et al. (1995) mapped the PPOX gene to 1q23 by FISH; furthermore, they showed that variegate porphyria is linked to DNA markers in the 1q21-q25 region. They concluded that the findings spoke against locus heterogeneity in VP. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Variegate Porphyria</em></strong></p><p>
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Deybach et al. (1996), Meissner et al. (1996), Warnich et al. (1996), and Lam et al. (1997) identified heterozygous mutations in the PPOX gene (see, e.g., 600923.0001-600923.0005) in patients with variegate porphyria (VP; 176200). </p><p>In 2 unrelated women with variegate porphyria, Frank et al. (1998) identified heterozygosity for the same missense mutation (R168H; 600923.0006). Segregation analysis revealed that an unaffected son of one of the probands also carried the R168H variant, which was not found in controls. </p><p>Wiman et al. (2003) stated that approximately 80 individuals from 28 apparently unrelated families had been diagnosed with VP in Sweden. Genetic analysis of the PPOX gene in 17 of these families identified 10 different mutations, only 1 of which had previously been reported. Mutation analysis in family members revealed 2 adults and 4 children who were silent carriers of the VP trait. </p><p>Borrero Corte et al. (2019) sequenced the PPOX gene in 8 unrelated Spanish patients with variegate porphyria, 4 of whom had only cutaneous photosensitivity, 3 of whom experienced only acute symptoms, and 1 of whom had both. The authors identified heterozygosity for known VP-associated mutations in all patients (see, e.g., 600923.0006). No genotype/phenotype correlations were observed. </p><p><strong><em>Childhood-Onset Variegate Porphyria</em></strong></p><p>
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In an Afrikaner girl with photosensitivity, severe brachydactyly, seizures, developmental delay, sensory neuropathy, and an abnormal porphyrin excretion pattern (VPCO; 620483), Meissner et al. (1996) identified compound heterozygosity for missense mutations in the PPOX gene: an R59W substitution (600923.0003) and an R168C substitution (600923.0004). Her mother, who met the criteria for VP, was heterozygous for the R59W mutation, and her father, who had normal porphyrin biochemistry and a 25% reduction in PPO activity, was heterozygous for the R168C variant. The authors also detected the R59W mutation in 43 of 45 patients with autosomal dominant VP (176200) from 26 of 27 South African families; genealogic analysis of 1 of the South African families demonstrated relatedness to the original South African VP family tree, suggesting a founder effect. Functional analysis of the R59W mutation demonstrated that the mutant enzyme had an almost undetectable catalytic rate but a relatively invariant K(m), consistent with the 50% reduction in PPO activity seen in the proband's mother. </p><p>In a 20-year-old woman with apparent autosomal recessive variegate porphyria, who in addition to cutaneous manifestations exhibited impaired intellectual development and hand deformities, Frank et al. (1998) identified compound heterozygosity for missense mutations in the PPOX gene: a G169E substitution (600923.0014) and a G358R substitution (600923.0015). Her asymptomatic parents, who both exhibited approximately half-normal levels of PPO activity, were each heterozygous for 1 of the mutations, neither of which was found in 50 unrelated controls. </p><p>Roberts et al. (1998) confirmed the molecular characterization of the rare 'homozygous' variant of variegate porphyria. They identified PPOX mutations on both alleles of 5 of the 11 unrelated patients with apparent autosomal recessive VP reported to that time. Two patients were homozygous for missense mutations (D349A, 600923.0007 and A433P), whereas 2 were compound heterozygous for a G358R substitution and either a G169E substitution or a splice site mutation, respectively, and the remaining patient was compound heterozygous for a 12-bp insertion and another splice site mutation. Functional analysis by prokaryotic expression showed that the D349A and A433P mutations and 1 missense mutation in each of the 3 heteroallelic patients (G538R in 2 patients and 657ins12) preserved some PPOX activity (9.5-25% of wildtype). Mutations on the other allele of the heteroallelic patients abolished or markedly decreased activity. There was no relation between genotype assessed by functional analysis and the presence or severity of noncutaneous manifestations. All the mutations found in the homozygous patients were absent from 104 unrelated patients with autosomal dominant VP. The authors concluded that mild PPOX mutations occur in the general population but have a very low or no clinical penetrance in heterozygotes. </p><p>In a 36-year-old British woman with severe cutaneous manifestations of variegate porphyria and brachydactyly, Palmer et al. (2001) identified compound heterozygosity for mutations in the PPOX gene: an in-frame 12-bp insertion (600923.0010) and a splice site mutation (600923.0011). The proband's mother, who was heterozygous for the splice site mutation, experienced 3 neuroabdominal episodes, 2 of which followed drug ingestion; she had no cutaneous manifestations. A maternal first cousin, who also carried the splice site mutation, was asymptomatic. DNA was unavailable from the proband's deceased father, who was reported to be asymptomatic. </p><p>In a Finnish boy with apparent homozygous variegate porphyria, Kauppinen et al. (2001) identified compound heterozygosity for 2 missense mutations in the PPOX gene: an I12T substitution (600923.0012) and a P256R substitution (600923.0013). Affected members of another Finnish family were compound heterozygous for the same mutations, suggesting a common ancestor. One heterozygous carrier in each family was mildly symptomatic. </p><p>In a 33-year-old Chinese man with childhood-onset variegate porphyria, Cho et al. (2021) sequenced the PPOX gene and identified homozygosity for a missense mutation (V270L; 600923.0018) at the first base of exon 8 of the PPOX gene. His unaffected consanguineous parents were heterozygous for the mutation. Functional analysis revealed that the mutation affected splicing, resulting in exon skipping that was predicted to result in a truncated protein. </p>
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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>18 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 VARIEGATE PORPHYRIA</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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PPOX, 1-BP INS, 1022G
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<br />
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SNP: rs1571369150,
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ClinVar: RCV000822922, RCV002271591
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient (P1) of French Caucasian origin with variegate porphyria (VP; 176200), Deybach et al. (1996) identified heterozygosity for a 1-bp insertion (c.1022insG) in exon 7 of the PPOX gene, producing a frameshift that resulted in a premature stop codon. </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>.0002 VARIEGATE PORPHYRIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
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|
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|
PPOX, GLY232ARG
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|
<br />
|
|
|
|
SNP: rs121918323,
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|
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|
|
ClinVar: RCV000009230, RCV000816933
|
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|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
<p>In 3 patients (P2-P4) from 2 unrelated French Caucasian families with variegate porphyria (VP; 176200), Deybach et al. (1996) found heterozygosity for a G-to-C transversion at nucleotide 971 (c.971G-C), resulting in a gly232-to-arg (G232R) substitution. In 1 of the families, consisting of 14 members over 3 generations, the authors demonstrated that the mutation segregated fully with deficient PPOX activity. </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>.0003 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
VARIEGATE PORPHYRIA, INCLUDED
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
|
PPOX, ARG59TRP
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<br />
|
|
|
|
SNP: rs121918324,
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|
|
ClinVar: RCV000009233, RCV001232723, RCV003324489
|
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|
|
</span>
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|
</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a girl of Afrikaner origin with photosensitivity, severe brachydactyly, seizures, developmental delay, sensory neuropathy, and an abnormal porphyrin excretion pattern (VPCO; 620483), who was originally described by Hift et al. (1993), Meissner et al. (1996) identified compound heterozygosity for missense mutations in the PPOX gene: a C-to-T transition in exon 3, resulting in an arg59-to-trp (R59W) substitution within the predicted FAD (see 610595) dinucleotide-binding motif, and a C-to-T transition in codon 168, resulting in an arg168-to-cys (R168C; 600923.0004) substitution. The proband's mother, who met the criteria for autosomal dominant VP (176200), was heterozygous for the R59W mutation, and her father, who had normal porphyrin biochemistry and a 25% reduction in PPO activity, was heterozygous for the R168C variant. The authors also detected the R59W substitution in 43 of 45 patients with VP from 26 of 27 South African families, but not in 34 unaffected relatives or 9 unrelated British patients with PPO deficiency. Genealogic analysis of 1 of the South African families demonstrated relatedness to the original South African VP family tree (Dean, 1972), suggesting a founder effect. Functional analysis of the R59W mutation demonstrated that the mutant enzyme had an almost undetectable catalytic rate but a relatively invariant K(m), consistent with the reduced PPO activity seen in the VP patients. </p><p>Warnich et al. (1996) identified heterozygosity for the R59W mutation (c.452C-T) in 15 of 17 South African patients with variegate porphyria. This mutation was shown to create a StyI restriction site in the gene. It was also shown to be associated with C(26)-C(150), 1 of 4 potential haplotypes defined by 2 polymorphisms in exon 1 of the PPOX gene. </p><p>De Villiers et al. (1999) identified a patient with severe variegate porphyria carrying the R59W allele of the PPOX gene who was also compound heterozygous for mutations in the HFE gene (Q127H, 235200.0007 and H63D, 235200.0002). The authors also found that the mutant allele frequency of the HFE C282Y mutation (235200.0001) was significantly lower in 73 apparently unrelated VP patients carrying the R59W mutation than in 102 controls drawn from the same population in South Africa (p = 0.005). The authors concluded that their findings supported data on the involvement of the HFE gene in the porphyria phenotype. </p><p>In a 7-year-old girl of Afrikaner origin (family 1) with severe cutaneous photosensitivity, brachydactyly, and sensory neuropathy, Corrigall et al. (2000) identified compound heterozygosity for the recurrent R59W mutation in the PPOX gene, and an A-to-G transition in exon 10, resulting in a tyr348-to-cys (Y348C; 600923.0016) substitution. Testing of 10 additional family members revealed heterozygosity for the R59W mutation in the proband's asymptomatic mother and 12-year-old sister; the mother showed a fecal porphyrin excretion pattern typical of VP, but the sister was biochemically negative. The proband's asymptomatic father, half brother, and half sister were heterozygous for the Y348C mutation; her father had a normal fecal porphyrin excretion profile but showed a small peak at 625 nm on plasma fluoroscanning, her half brother had a typical VP fecal porphyrin excretion pattern but normal plasma fluoroscan, and her half sister was biochemically negative. The Y348C mutation was shown to have arisen de novo in the father. In 2 South African sisters of mixed-race origin (family 2), 1 of whom experienced acute porphyric attacks and severe cutaneous photosensitivity and the other of whom showed typical VP skin disease, Corrigall et al. (2000) identified compound heterozygosity for R59W in PPOX and a R138P mutation (600923.0017). None of the mutations was found in 50 ethnically matched controls. Noting that the sisters who were compound heterozygous for the R59W and R138P mutations did not manifest symptoms in early childhood, the authors suggested that the R138P mutation might have more residual PPO activity than the Y438C mutation. </p>
|
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</span>
|
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</div>
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<div>
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<br />
|
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</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
VARIEGATE PORPHYRIA, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PPOX, ARG168CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918325,
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|
|
|
|
|
gnomAD: rs121918325,
|
|
|
|
|
|
ClinVar: RCV000009231, RCV003324488
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the C-to-T transition in codon 168 of the PPOX gene, resulting in an arg168-to-cys (R168C) substitution, that was found in compound heterozygous state in a girl of Afrikaner origin with childhood-onset variegate porphyria (VPCO; 620483) by Meissner et al. (1996), see 600923.0003. </p><p>Warnich et al. (1996) identified heterozygosity for this exon 6 mutation (R168C) in the PPOX gene in 1 of 17 South African patients with variegate porphyria (VP; 176200). This mutation would abolish a DsaI restriction site in genomic DNA of affected individuals, and was shown to be associated with a different haplotype for the exon 1 polymorphism A(26)-C(150) than were the R59W (600923.0003) or H20P (600923.0005) mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 VARIEGATE PORPHYRIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PPOX, HIS20PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918326,
|
|
|
|
|
|
|
|
ClinVar: RCV000009232
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 of 17 unrelated patients with variegate porphyria (VP; 176200) from South Africa, Warnich et al. (1996) identified heterozygosity for a c.336A-C transversion in exon 2 of the PPOX gene that resulted in a his20-to-pro (H20P) amino acid substitution. The mutation was associated with the same exon 1 polymorphism haplotype as the R59W mutation (600923.0003). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 VARIEGATE PORPHYRIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PPOX, ARG168HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs41270025,
|
|
|
|
|
|
|
|
ClinVar: RCV000009234, RCV000492944, RCV002251893
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 57-year-old woman (proband 1) and an unrelated 38-year-old woman (proband 2) with variegate porphyria (VP; 176200), Frank et al. (1998) identified a c.502G-A transition in exon 6 of the PPOX gene, resulting in an arg168-to-his (R168H) substitution at a highly conserved residue. The mutation occurred in the same codon as the previously reported arg168-to-cys mutation (R168C; 600923.0004) and, noting that the mutation involved a putatively hypermutable CpG dinucleotide, the authors suggested that R168 might be a mutational hotspot. Segregation analysis in the family of proband 1 revealed that her unaffected son also carried the R168H variant, indicating incomplete penetrance; relatives of proband 2 were unavailable for study. The mutation was not found in 50 unrelated controls. </p><p>Frank et al. (2001) found the same R168H mutation on separate haplotypes in 6 VP patients from 3 unrelated families in Chile. The authors suggested that R168H is a hotspot mutation. </p><p>In 2 unrelated Spanish women with VP, including an 18-year-old (patient 2) with only cutaneous photosensitivity and a 64-year-old (patient 3) with only acute symptoms, Borrero Corte et al. (2019) identified heterozygosity for the previously reported R168H mutation in the PPOX gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PPOX, ASP349ALA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28936676,
|
|
|
|
|
|
|
|
ClinVar: RCV003324490
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy (patient 3) with childhood-onset variegate porphyria (VPCO; 620483), Roberts et al. (1998) found homozygosity for a c.1046A-C transversion in exon 10 of the PPOX gene, resulting in an asp349-to-ala (D349A) substitution. The patient, a 16-year-old male at the time of study, was the offspring of consanguineous Lebanese parents and had developed severe skin lesions from the age of 8 months. The diagnosis of homozygous VP was made at the age of 7 years. The patient had no mental retardation, convulsions, nystagmus, or growth retardation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 VARIEGATE PORPHYRIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PPOX, 2-BP DEL, 537AT
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1571357779,
|
|
|
|
|
|
|
|
ClinVar: RCV000009236
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 31-year-old South African woman of mixed racial ancestry with variegate porphyria (VP; 176200), Corrigall et al. (1998) identified a heterozygous 2-bp deletion in exon 6, c.537delAT, which resulted in a premature stop codon 11 codons downstream. The mutation was also found in her affected cousin. Among 31 family members tested, 17 were found to carry the mutation; 13 of these 17 showed biochemical evidence of VP in urine and stool porphyrin analysis, whereas the other 4 had normal porphyrin excretion patterns. Only 3 of the 17 were symptomatic. This rare variant was the first reported deletion in the PPOX gene in a South African family. Corrigall et al. (1998) noted that the great majority of South African patients with VP carry the R59W mutation of the PPOX gene (600923.0003). H20P (600923.0005) and R168C (600923.0004) are uncommon mutations in South African families. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 VARIEGATE PORPHYRIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PPOX, 5-BP DEL, NT1239
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2101902523,
|
|
|
|
|
|
|
|
ClinVar: RCV000009237
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Frank et al. (2001) found an apparent founder mutation, c.1239delTACAC, on the same chromosome 1 haplotype in 11 mutation carriers from 4 Chilean families with variegate porphyria (VP; 176200). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PPOX, 12-BP INS, NT657
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2101876868,
|
|
|
|
|
|
|
|
ClinVar: RCV003324491
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 36-year-old British woman with severe cutaneous manifestations of variegate porphyria and brachydactyly (VPCO; 620483), Palmer et al. (2001) identified compound heterozygosity for mutations in the PPOX gene: an in-frame 12-bp insertion (c.657-658insAAGGCCAGCGCC), encoding 4 additional amino acid residues (KASA), and a splice site mutation at the donor site of exon 11 (IVS11-1G-A; 600923.0011). The proband's mother, who was heterozygous for the splice site mutation, experienced 3 neuroabdominal episodes, 2 of which followed drug ingestion (VP; 176200); she had no cutaneous manifestations. A maternal first cousin, who also carried the splice site mutation, was asymptomatic. DNA was unavailable from the proband's deceased father, who was reported to be asymptomatic. The patient had onset of skin fragility, scarring, and blisters on sun-exposed sites at 9 months of age. She experienced a febrile convulsion at 4 years of age, had delayed bone age at 19 years of age, and was of short stature. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
VARIEGATE PORPHYRIA, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PPOX, IVS11DS, G-A, -1
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV003324492, RCV003324493
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For a discussion of the IVS11-1G-A mutation in the PPOX gene that was found in compound heterozygous state in a woman with childhood-onset variegate porphyria (VPCO; 620483) by Palmer et al. (2001), see 600923.0010. The mutation had been transmitted by her mother, who had experienced 3 neuroabdominal porphyric episodes, 2 of which followed drug ingestion (VP; 176200); she had no cutaneous manifestations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
VARIEGATE PORPHYRIA, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PPOX, ILE12THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28936677,
|
|
|
|
|
|
gnomAD: rs28936677,
|
|
|
|
|
|
ClinVar: RCV003324494, RCV003324495
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Finnish boy with childhood-onset variegate porphyria (VPCO; 620483), originally described by Mustajoki et al. (1987), Kauppinen et al. (2001) identified compound heterozygosity for mutations in the PPOX gene: a c.35T-C transition in exon 2 of the PPOX gene, resulting in an ile12-to-thr (I12T) substitution, and a c.767C-G transversion in exon 7, resulting in a pro256-to-arg (P256R; 600923.0013) substitution. His asymptomatic first-cousin parents and his grandmothers were heterozygous for the mutations. Mustajoki et al. (1987) reported that 1 of the grandmothers was mildly affected, experiencing blistering on exposed skin in the summer with residual scarring. Affected members of another Finnish family were compound heterozygous for the same mutations, suggesting a common ancestor. Kauppinen et al. (2001) noted that 1 heterozygous carrier of the I12T mutation in the second Finnish family had experienced 2 acute attacks in her youth associated with sulfonamides. Expression of the mutant enzymes in E. coli and COS-1 cells showed that the I12T mutation resulted in loss of enzyme function, whereas the P256R mutation resulted in less than half of normal PPOX activity in the prokaryotic system and almost normal activity in the eukaryotic cells. Kauppinen et al. (2001) noted that the P256R change had been identified as a polymorphism in western European populations (Whatley et al., 1999). </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 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</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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PPOX, PRO256ARG
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<br />
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SNP: rs12735723,
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gnomAD: rs12735723,
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ClinVar: RCV000961007, RCV000986448, RCV003324496, RCV003924820
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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 c.767C-G transition in exon 7 of the PPOX gene, resulting in a pro256-to-arg (P256R) substitution, that was found in compound heterozygous state in affected members of 2 Finnish families with childhood-onset variegate porphyria (VPCO; 620483) by Kauppinen et al. (2001), see 600923.0012. </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 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</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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PPOX, GLY169GLU
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<br />
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ClinVar: RCV003324652
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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 20-year-old woman with childhood-onset variegate porphyria (VPCO; 620483), originally described by Norris et al. (1990), who in addition to cutaneous manifestations exhibited impaired intellectual development and hand deformities, Frank et al. (1998) identified compound heterozygosity for missense mutations in the PPOX gene: a c.505G-A transition in exon 6, resulting in a gly169-to-glu (G169E) substitution at a highly conserved residue, and a c.1071G-A transition in exon 10, resulting in a gly358-to-arg (G358R; 600923.0015) substitution at a conserved residue. Her asymptomatic parents were each heterozygous for 1 of the mutations, neither of which was found in 50 unrelated controls. Frank et al. (1998) noted that the patient had PPO activity that was less than 20% of normal, whereas both parents had approximately half-normal levels of PPO activity. </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 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</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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PPOX, GLY358ARG
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<br />
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SNP: rs374936130,
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gnomAD: rs374936130,
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ClinVar: RCV001169976, RCV001339128, RCV003328475
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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 c.1071G-A transition in exon 10 of the PPOX gene, resulting in a gly358-to-arg (G358R) substitution, that was found in compound heterozygous state in a 20-year-old woman with childhood-onset variegate porphyria (VPCO; 620483) by Frank et al. (1998), see 600923.0014. </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>.0016 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</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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PPOX, TYR348CYS
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<br />
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ClinVar: RCV003324654
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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 A-to-G transition in exon 10 of the PPOX gene, resulting in a tyr348-to-cys (Y348C) substitution, that was found in compound heterozygous state in a 7-year-old girl of Afrikaner origin (family 1) with childhood-onset variegate porphyria (VPCO; 620483) by Corrigall et al. (2000), see 600923.0003. </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>.0017 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</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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PPOX, ARG138PRO
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<br />
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ClinVar: RCV003324655
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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 G-to-C transversion in exon 5 of the PPOX gene, resulting in an arg138-to-pro (R138P) substitution, that was found in compound heterozygous state in 2 South African sisters of mixed-race origin (family 2) with childhood-onset variegate porphyria (VPCO; 620483) by Corrigall et al. (2000), see 600923.0003. </p>
|
|
</span>
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|
</div>
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|
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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>.0018 VARIEGATE PORPHYRIA, CHILDHOOD-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
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|
|
PPOX, VAL270LEU
|
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<br />
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|
|
ClinVar: RCV003324656
|
|
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|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 33-year-old Chinese man with childhood-onset variegate porphyria (VRCO; 620483), Cho et al. (2021) identified homozygosity for a c.808G-T transversion (c.808G-T, NM_000309.3) at the first base of exon 8 in the PPOX gene, resulting in a val270-to-leu (V270L) substitution. His unaffected consanguineous parents were heterozygous for the mutation, which was not found in the gnomAD v.2.1.1 database. Functional analysis in transfected HEK293 cells revealed only a 200-bp band similar to the vector-only control, with absence of the normal 300-bp product, suggesting aberrant splicing. Sanger sequencing confirmed skipping of exon 8, causing a frameshift predicted to result in a premature termination codon (Val270CysfsTer17). </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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|
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|
<div>
|
|
<ol>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Borrero Corte, M. J., Jara Rubio, F., Moran Jimenez, M. J., Diaz Diaz, S., Castelbon Fernandez, F. J., Garcia Pastor, I., Enriquez de Salamanca, R., Mendez, M.
|
|
<strong>Molecular analysis of 19 Spanish patients with mixed porphyrias.</strong>
|
|
Europ. J. Med. Genet. 62: 103589, 2019.
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[PubMed: 30476629]
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[Full Text: https://doi.org/10.1016/j.ejmg.2018.11.023]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Cho, S. Y., Lau, E. Y.-T., Luk, D. C.-K., Law, C.-Y., Lai, C.-K., Lam, C.-W.
|
|
<strong>Novel PPOX exonic mutation inducing aberrant splicing in a patient with homozygous variegate porphyria.</strong>
|
|
Clin. Chim. Acta 512: 117-120, 2021.
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[PubMed: 33159949]
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[Full Text: https://doi.org/10.1016/j.cca.2020.10.033]
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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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Corrigall, A. V., Hift, R. J., Davids, L. M., Hancock, V., Meissner, D., Kirsch, R. E., Meissner, P. N.
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<strong>Homozygous variegate porphyria in South Africa: genotypic analysis in two cases.</strong>
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Molec. Genet. Metab. 69: 323-330, 2000.
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[PubMed: 10870850]
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[Full Text: https://doi.org/10.1006/mgme.2000.2975]
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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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Corrigall, A. V., Hift, R. J., Hancock, V., Meissner, D., Davids, L., Kirsch, R. E., Meissner, P. N.
|
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<strong>Identification and characterisation of a deletion (537delAT) in the protoporphyrinogen oxidase gene in a South African variegate porphyria family.</strong>
|
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Hum. Mutat. 12: 403-407, 1998.
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[PubMed: 9829909]
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[Full Text: https://doi.org/10.1002/(SICI)1098-1004(1998)12:6<403::AID-HUMU6>3.0.CO;2-X]
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de Villiers, J. N. P., Hillermann, R., Loubser, L., Kotze, M. J.
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<strong>Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria.</strong>
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Hum. Molec. Genet. 8: 1517-1522, 1999. Note: Erratum: Hum. Molec. Genet. 8: 1817 only, 1999.
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[PubMed: 10401000]
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[Full Text: https://doi.org/10.1093/hmg/8.8.1517]
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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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Dean, G.
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<strong>The Porphyrias. A Story of Inheritance and Environment.</strong>
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Philadelphia: J. B. Lippincott (pub.) 1972.
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<li>
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<p class="mim-text-font">
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Deybach, J.-C., Puy, H., Robreau, A.-M., Lamoril, J., Da Silva, V., Grandchamp, B., Nordmann, Y.
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<strong>Mutations in the protoporphyrinogen oxidase gene in patients with variegate porphyria.</strong>
|
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Hum. Molec. Genet. 5: 407-410, 1996.
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[PubMed: 8852667]
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[Full Text: https://doi.org/10.1093/hmg/5.3.407]
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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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Frank, J., Aita, V. M., Ahmad, W., Lam, H., Wolff, C., Christiano, A. M.
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<strong>Identification of a founder mutation in the protoporphyrinogen oxidase gene in variegate porphyria patients from Chile.</strong>
|
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Hum. Hered. 51: 160-168, 2001.
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[PubMed: 11173967]
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[Full Text: https://doi.org/10.1159/000053337]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Frank, J., Jugert, F. K., Breitkopf, C., Goerz, G., Merk, H. F., Christiano, A. M.
|
|
<strong>Recurrent missense mutation in the protoporphyrinogen oxidase gene underlies variegate porphyria.</strong>
|
|
Am. J. Med. Genet. 79: 22-26, 1998.
|
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|
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[PubMed: 9738863]
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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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Frank, J., McGrath, J., Lam, H., Graham, R. M., Hawk, J. L. M., Christiano, A. M.
|
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<strong>Homozygous variegate porphyria: identification of mutations on both alleles of the protoporphyrinogen oxidase gene in a severely affected proband.</strong>
|
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J. Invest. Derm. 110: 452-455, 1998.
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[PubMed: 9540991]
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[Full Text: https://doi.org/10.1046/j.1523-1747.1998.00148.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Hift, R. J., Meissner, P. N., Todd, G., Kirby, P., Bilsland, D., Collins, P., Ferguson, J., Moore, M. R.
|
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<strong>Homozygous variegate porphyria: an evolving clinical syndrome.</strong>
|
|
Postgrad. Med. J. 69: 781-786, 1993. Note: Erratum: Postgrad. Med. J. 70: 855 only, 1994.
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[PubMed: 8290408]
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[Full Text: https://doi.org/10.1136/pgmj.69.816.781]
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|
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</p>
|
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Kauppinen, R., Timonen, K., von und zu Fraunberg, M., Laitinen, E., Ahola, H., Tenhunen, R., Taketani, S., Mustajoki, P.
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<strong>Homozygous variegate porphyria: 20 y follow-up and characterization of molecular defect.</strong>
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J. Invest. Derm. 116: 610-613, 2001.
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[PubMed: 11286631]
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[Full Text: https://doi.org/10.1046/j.1523-1747.2001.01293.x]
|
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|
|
</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Lam, H., Dragan, L., Tsou, H. C., Merk, H., Peacocke, M., Goerz, G., Sassa, S., Poh-Fitzpatrick, M., Bickers, D. R., Christiano, A. M.
|
|
<strong>Molecular basis of variegate porphyria: a de novo insertion mutation in the protoporphyrinogen oxidase gene.</strong>
|
|
Hum. Genet. 99: 126-129, 1997.
|
|
|
|
|
|
[PubMed: 9003509]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s004390050325]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Meissner, P. N., Dailey, T. A., Hift, R. J., Ziman, M., Corrigall, A. V., Roberts, A. G., Meissner, D. M., Kirsch, R. E., Dailey, H. A.
|
|
<strong>A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria.</strong>
|
|
Nature Genet. 13: 95-97, 1996.
|
|
|
|
|
|
[PubMed: 8673113]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng0596-95]
|
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Mustajoki, P., Tenhunen, R., Niemi, K. M., Nordmann, Y., Kaariainen, H., Norio, R.
|
|
<strong>Homozygous variegate porphyria: a severe skin disease of infancy.</strong>
|
|
Clin. Genet. 32: 300-305, 1987.
|
|
|
|
|
|
[PubMed: 3319294]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/j.1399-0004.1987.tb03294.x]
|
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Nishimura, K., Taketani, S., Inokuchi, H.
|
|
<strong>Cloning of a human cDNA for protoporphyrinogen oxidase by complementation in vivo of a hemG mutant of Escherichia coli.</strong>
|
|
J. Biol. Chem. 270: 8076-8080, 1995.
|
|
|
|
|
|
[PubMed: 7713909]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.270.14.8076]
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Norris, P. G., Elder, G. H., Hawk, J. L. M.
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Palmer, R. A., Elder, G. H., Barrett, D. F., Keohane, S. G.
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Puy, H., Robreau, A.-M., Rosipal, R., Nordmann, Y., Deybach, J.-C.
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<strong>Protoporphyrinogen oxidase: complete genomic sequence and polymorphisms in the human gene.</strong>
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Roberts, A. G., Puy, H., Dailey, T. A., Morgan, R. R., Whatley, S. D., Dailey, H. A., Martasek, P., Nordmann, Y., Deybach, J.-C., Elder, G. H.
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<strong>Molecular characterization of homozygous variegate porphyria.</strong>
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Roberts, A. G., Whatley, S. D., Daniels, J., Holmans, P., Fenton, I., Owen, M. J., Thompson, P., Long, C., Elder, G. H.
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<strong>Partial characterization and assignment of the gene for protoporphyrinogen oxidase and variegate porphyria to human chromosome 1q23.</strong>
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<strong>The human protoporphyrinogen oxidase gene (PPOX): organization and location to chromosome 1.</strong>
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Warnich, L., Kotze, M. J., Groenewald, I. M., Groenewald, J. Z., van Brakel, M. G., van Heerden, C. J., de Villiers, J. N. P., van de Ven, W. J. M., Schoenmakers, E. F. P. M., Taketani, S., Retief, A. E.
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<strong>Identification of three mutations and associated haplotypes in the protoporphyrinogen oxidase gene in South African families with variegate porphyria.</strong>
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Whatley, S. D., Puy, H., Morgan, R. R., Robreau, A.-M., Roberts, A. G., Nordmann, Y., Elder, G. H., Deybach, J.-C.
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<strong>Variegate porphyria in Western Europe: identification of PPOX gene mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation.</strong>
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Wiman, A., Harper, P., Floderus, Y.
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<strong>Nine novel mutations in the protoporphyrinogen oxidase gene in Swedish families with variegate porphyria.</strong>
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Victor A. McKusick : 11/7/1995
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